Hydroquinone derivatives and intermediates for production thereof

ABSTRACT

There are disclosed novel hydroquinone derivatives of the formulas: ##STR1## The derivatives of the formula (I) have various pharmacological activities such as antioxidation in living bodies and are useful as medicaments, and the derivatives of the formula (II) are intermediates for the production thereof.

FIELD OF THE INVENTION

The present invention relates to novel hydroquinone derivatives whichhave various pharmacological activities such as antioxidation in livingbodies and are useful as medicaments, and intermediates for theproduction thereof.

BACKGROUND OF THE INVENTION

The present inventors have studied the chemical modification ofhydroquinone compounds which can readily be obtained from quinonecompounds in order to solubilize in water various biologically activequinone compounds useful as medicaments, to convert them into prodrugsor to find novel pharmacological activities of these derivativesthemselves.

However, in general, it is difficult to chemically modify the hydroxygroup of hydroquinone compounds regioselectively at any desired site.Thus, means to synthesize their various derivatives regioselectively isrequired.

OBJECTS OF THE INVENTION

Under these circumstances, the present inventors have intensivelystudied the regioselective introduction of a protecting group into thehydroxyl group of hydroquinone derivatives, selected silyl derivativesas a protecting group which can be removed under mild conditions andexamined the utilization of various silylating agents in considerationof the steric hindrance between reaction substrates and silyl groups tobe introduced. As a result, it has been found that (1) thetert-butyldiphenylsilyl group is introduced into the less hinderedhydroxyl group of hydroquinone derivatives in high selectivity, and (2)by using compounds obtained by introducing an appropriate protectinggroup into the compounds or free hydroxyl group of the compoundsfollowed by removal of the tert-butyldiphenylsilyl group, any desiredhydroxyl group of hydroquinone derivatives can be chemically-modifiedregioselectively. Thus, the present invention has been completed.

One object of the present invention is to provide novel hydroquinonederivatives useful as medicaments wherein any desired hydroxyl in thebenzene ring is chemically modified regioselectively.

Another object of the present invention is to provide novel hydroquinonecompounds wherein the hydroxyl at the 4-position is protectedregio-selectively. These compounds are useful as intermediates for theproduction of the above hydroquinone derivatives.

These objects as well as other objects and advantages of the presentinvention will become apparent to those skilled in the art from thefollowing description.

SUMMARY OF THE INVENTION

According to the present invention, there are provided:

(1) A hydroquinone derivative of the formula (I): ##STR2## wherein R¹and R² are the same or different and are methyl or methoxy, or R¹ and R²are joined together to form the group of the formula: --CH═CH--CH═CH--;one of A and B is optionally substituted alkyl, acyl, alkoxycarbonyl,optionally O-acylated and/or optionally esterified glycosyl, sulfo orphosphono, and the other is hydrogen; X is hydrogen, aryl orheterocyclic group; R is saturated or unsaturated bivalentstraight-chain hydrocarbon group having 1 to 20 carbon atoms or achemical bond, provided that, when X is hydrogen, R is a saturated orunsaturated bivalent straight-chain hydrocarbon group having 1 to 20carbon atoms; and Y is hydrogen, optionally esterified or optionallyamidated carboxyl or optionally substituted hydroxymethyl, providedthat, when X is hydrogen and one of A and B is sulfo, Y is hydrogen and,when X is hydrogen and one of A and B is optionally O-acylated and/oroptionally esterified glycosyl, Y is hydrogen or optionally substitutedhydroxymethyl; and a pharmaceutically acceptable salt, and

(2) A compound of the formula (II): ##STR3## wherein R¹ and R² are thesame or different and are hydrogen, methyl or methoxy, or R¹ and R² arejoined together to form the group of the formula: --CH═CH--CH═CH--; R³is hydrogen or a protecting group other than silyl; X is hydrogen, arylor heterocyclic group; R is a saturated or unsaturated bivalentstraight-chain hydrocarbon group having 1 to 20 carbon atoms or achemical bond; Y is hydrogen, optionally substituted hydroxymethyl oroptionally esterified or optionally amidated carboxyl; Ph is phenyl; andt-Bu is tert-butyl.

As examples of the optionally substituted alkyl represented by A or B inthe above formulas (I) and (II), there are lower alkyl having 1 to 4carbon atoms such as methyl, ethyl, propyl, butyl or the like;carboxymethyl; pyridylmethyl; and benzyl.

Examples of the acyl represented by A or B include aliphatic acyl having1 to 4 carbon atoms such as formyl, acetyl, propionyl or butyryl;aromatic acyl such as benzoyl, picolinoyl, nicotinoyl, isonicotinoyl orthe like; glycyl; β-aspartyl; γ-glutamyl and 3-carboxypropionyl.

Examples of the alkoxycarbonyl include that having 2 to 5 carbon atomssuch as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,isobutoxycarbonyl, t-butoxycarbonyl or the like.

Examples of the glycosyl represented by A or B include glucosyl,rhamnosyl, sucrosyl, glucuronosyl and the like. When the hydroxy ofthese saccharides is O-acylated, examples of the acyl include aliphaticacyl such as acetyl; and aromatic acyl such as benzoyl, p-methylbenzoyland nicotinoyl. When the carboxy of the saccharide residues isesterified, alkyl esters are preferred. Examples of the alkyl includethat having 1 to 4 carbon atoms such as methyl, ethyl, propyl or butyl.

Examples of the aryl represented by X include phenyl, naphthyl and thelike. The aryl may have one or more substituents at any position on thering. Examples of the substituent include alkyl having 1 to 3 carbonatoms such as methyl, ethyl or the like; alkoxy having 1 to 3 carbonatoms such as methoxy, ethoxy or the like; halogen atoms such aschlorine, fluorine, bromine or the like; and the like.

As examples of the heterocyclic group represented by X, there are 5 or 6membered rings containing, as an atom constituting the ring, one or morehetero atoms selected from oxygen, sulfur and nitrogen. Examples of theheterocyclic group include aromatic heterocyclic groups such as thienyl,furyl, pyridyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl or thelike; and saturated heterocyclic groups such as morpholino,thiomorpholino, piperidino, pyrrolidino, piperazino or the like. Thesegroups may have one or more substituents at any position on the ring.Examples of the substituent include alkyl having 1 to 3 carbon atomssuch as methyl, ethyl or the like; alkoxy having 1 to 3 carbon atomssuch as methoxy, ethoxy or the like; halogen atoms such as chlorine,fluorine, bromine or the like; and the like.

As examples of the optionally substituted hydroxymethyl represented byY, there are unsubstituted hydroxymethyl, methoxymethyloxymethyl,acetoxymethyl, nitroxymethyl, aminocarbonyloxymethyl, substitutedaminocarbonyloxymethyl (e.g., methylaminocarbonyloxymethyl,ethylaminocarbonyloxymethyl, dimethylaminocarbonyloxymethyl,phenylaminocarbonyloxymethyl, etc.), cyclic aminocarbonyloxymethyl(e.g., morpholinocarbonyloxymethyl, piperidinocarbonyloxymethyl, etc.)and the like.

Examples of the optionally esterified carboxyl represented by Y includealkoxycarbonyl having 2 to 5 carbon atoms such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or the like;aryloxycarbonyl having 7 to 8 carbon atoms such as phenoxycarbonyl orthe like.

The optionally amidated carboxyl represented by Y may be substitutedaminocarbonyl whose amino group is substituted or may be cyclicaminocarbonyl. As examples of the substituent of the amino group of thesubstituted aminocarbonyl, there are alkyl having 1 to 4 carbon atomssuch as methyl, ethyl, propyl, butyl or the like; aryl having 6 to 10carbon atoms such as phenyl, naphthyl or the like (these may furtherhave one or more substituents such as hydroxyl, amino, nitro, halogen,methyl, methoxy or the like at any position on the ring); hydroxyl andthe like. Examples of the amidated carboxyl include aminocarbonyl, mono-or dialkylaminocarbonyl having 2 to 4 carbon atoms (e.g.,methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl,dimethylaminocarbonyl, etc.), phenylaminocarbonyl, substitutedphenylaminocarbonyl (e.g., p-hydroxyphenylaminocarbonyl,p-methoxyphenylaminocarbonyl, m-chlorophenylaminocarbonyl, etc.),diphenylaminocarbonyl, hydroxyaminocarbonyl,N-hydroxy-N-methylaminocarbonyl, N-hydroxy-N-phenylaminocarbonyl and thelike. Examples of the cyclic aminocarbonyl include morpholinocarbonyl,thiomorpholinocarbonyl, piperidinocarbonyl or the like.

As examples of the saturated or unsaturated bivalent straight-chainhydrocarbon group having 1 to 20 carbon atoms represented by R, thereare pentamethylene, hexamethylene, heptamethylene, octamethylene,deca-1,6 -diynylene or the like.

The protecting group of hydroxy other than silyl represented by R³ inthe formula (II) is not specifically limited so long as it hasreactivities different from those of silyl, and there can be used anyprotecting group generally used in the field of organic synthesis.Examples thereof include lower aliphatic acyl such as acetyl, propionylor butyryl; aromatic acyl such as benzoyl or nicotinoyl; loweralkoxymethyl such as tetrahydropyranyl, methoxymethyl, ethoxyethyl,methoxyethoxymethyl or the like; lower alkylthiomethyl such asmethylthiomethyl; arylmethyl such as trityl and the like.

As examples of the pharmaceutically acceptable salt of the compound ofthe formula (I), there are salts with alkaline metal such as sodium,potassium or the like; salts with aluminum; salts with zinc; salts withammonium; and salts with organic amines.

Both R¹ and R² in the formula (I) are preferably methyl or both arepreferably methoxy. One of A and B in the formula (I) is preferablyphosphono, acyl, sulfo, or optionally O-acylated and/or optionallyesterified glycosyl. X in the formula (I) is preferably hydrogen oroptionally substituted phenyl. R in the formula (I) is preferably asaturated or unsaturated bivalent straight-chain hydrocarbon grouphaving 5 to 8 carbon atoms. Y in the formula (I) is preferablyhydroxymethyl, or optionally esterified or optionally amidated carboxyl.

In particular, the compounds of the formula (I) wherein both R¹ and R²are methyl, X is phenyl, and Y is an optionally esterified or optionallyamidated carboxyl, preferably unsubstituted carboxyl; and wherein bothR¹ and R² are methoxy, X is hydrogen, and Y is an optionally substitutedhydroxymethyl, preferably unsubstituted hydroxymethyl are preferable.

Preferred examples of the compound of the formula (I) include:

2,3-Dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl-1-phosphate;

2,3-Dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl-4-phosphate;

2,3-Dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methyl-1-(N-methyl-1,4-dihydropyridin-3-ylcarbonyloxy)benzene;

6-(6-Carboxy-1-phenylhexyl)-4-hydroxy-2,3,5-trimethylphenyl-1-O-β-D-glucopyranosiduronate;

6-(6-Carboxy-1-phenylhexyl)-1-hydroxy-2,3,5-trimethylphenyl-4-sulfate;and

6-(6-Carboxy-1-phenylhexyl)-1-hydroxy-2,3,5-trimethylphenyl-4-O-β-D-glucopyranosiduronate.

R¹ and R² in the formula (II) are preferably methyl or methoxy. X in theformula (II) is preferably hydrogen or optionally substituted phenyl. Rin the formula (II) is preferably a saturated or unsaturated bivalentstraight-chain hydrocarbon group having 5 to 8 carbon atoms. Y in theformula (II) is preferably hydroxymethyl, or optionally esterified oroptionally amidated carboxyl.

In particular, the compound of the formula (II) wherein both R¹ and R²are methyl, X is phenyl, and Y is optionally esterified or optionallyamidated carboxyl is preferable.

Preferred examples of the compound of the formula (II) include:

6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol;

4-tert-Butyldiphenylsilyloxy-2,3-dimethoxy-5-methyl-6-(10-trityloxydecyl)phenol;and

4-tert-Butyldiphenylsilyloxy-1-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene.

The compound of the formula (II) of the present invention which is animportant synthetic intermediate can be obtained by introducingtert-butyldiphenylsilyl into the corresponding hydroquinone derivativeof the formula (III): ##STR4## wherein each symbol is as defined above,according to the method of E. J. Corey et al. (J. Am. Chem. Soc., 94,6190, 1972). Namely, the hydroquinone derivative of the formula (III) isreacted with imidazole and tert-butyldiphenylsilyl chloride in an amountof 1 to 3 equivalents, preferably 1.5 to 2 equivalents in an inertsolvent such as dioxane, tetrahydrofuran, chloroform, dichloromethane,1,2-dichloroethane, dimethylformamide or the like, preferably indichloromethane. The reaction temperature is 0° C. to 80° C., preferably40° C. The reaction time is 2 to 20 hours. In this case,tert-butyldiphenylsilyl is introduced preferentially into the lesshindered hydroxyl at the 4position in high selectivity of 96:4. Theremainder being 4% is introduced into the 1-position. However, since itcan be converted to the corresponding 1,4-disilyl derivative with theexcess silylating agent, it can be separated readily by conventionalseparation methods such as column chromatography on silica gel or thelike. For example, the regio-selectivities of other silylating agentspreferentially introduced into the 4-position are as follows:triphenylsilyl ( 7:5), tert-butyldimethylsilyl (3:1), triisopropylsilyl(3:1), dimethylthexylsilyl (i.e. dimethyl(1,1,2-trimethylpropyl)silyl)(4:1).

The 4-tert-butyldiphenylsilyl derivative of the hydroquinone compoundthus obtained can be subjected to alkylation, acylation, glycosylation,sulfation or phosphorylation followed by removal of thetert-butyldiphenylsilyl at the 4-position to obtain the corresponding1-derivative as shown in Scheme 1. Further, an appropriate protectinggroup is introduced into the hydroxyl at the 1-position of the syntheticintermediate of the formula (II) wherein R³ is hydrogen, then thetert-butyldiphenylsilyl at the 4-position is removed and the hydroxyl atthe 4-position is alkylated, acylated, glycosylated, sulfated orphosphorylated followed by removal of the protecting group of thehydroxyl at the 1-position to obtain the corresponding 4-derivative.##STR5## wherein each symbol is as defined above.

The alkyl derivative of hydroquinone of the above formula (I) of thepresent invention can be obtained by subjecting the syntheticintermediate of the formula (II) to alkylation followed by desilylation,or by protecting the synthetic intermediate of the formula (II) withlower aliphatic acyl such as acetyl followed by desilylation, alkylationand then deacylation to give the corresponding 1- or 4-alkyl derivative,regio-selectively. The alkylation can be carried out in an inert solventby using a lower aklyl halide and tertiary organic amine and the likeaccording to conventional methods.

The acyl derivative of hydroquinone of the above formula (I) can beobtained by subjecting the synthetic intermediate of the formula (II) todesilylation followed by acylation, or by introducing a protecting groupreadily removable such as methoxyethoxymethyl into the syntheticintermediate of the formula (II) followed by desilylation, acylation andthen deprotection to give the corresponding 1- or 4-acyl derivative,regio-selectively.

The acylation can be carried out in an inert solvent according toconventional methods by using an acyl halide, an acid anhydride or thelike together with a tertiary organic amine, or a carboxylic acidderivative activated by acylimidazole such as 1,1'-carbonyldiimidazole.

The hydroquinone glycosyl derivative of the formula (I) of the presentinvention can be prepared by reacting the synthetic intermediate of theformula (II) with O-glycosyltrichloroacetimidate of the formula (IV):

    Gly--X                                                     (IV)

wherein Gly is the above O-acylated and/or esterified glycosyl residueand X is trichloroacetimidoyl (when R³ of the synthetic intermediate ofthe formula (II) is a protecting group, this reaction is carried outafter desilylation) according to a per se known method (R. R. Schmidt),Angew. Chem. Int. Ed. Engl., 25, 212 (1986)) followed by deprotection.As the O-acyl group in the compound (IV), lower aliphatic acyl such asacetyl is preferred. As the ester group, lower alkyl such as methyl ispreferred. Examples of the compound (IV) includeO-acetyl-α-glycopyranosyltrichloroacetimidate,O-acetyl-α-galactopyranosyltrichloroacetimidate andO-acetyl-α-mannopyranosyltrichloroacetimidate described in the abovepaper and methyl2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-α-D-glycopyranuronate (B.Fischer et al., J. Org. Chem., 49, 4988 (1984.)).

In this reaction, a Lewis acid is used as a catalyst in an inertsolvent. As the Lewis acid to prevent the production of thecorresponding α-anomer as a by-product, boron trifluoride diethyl ethercomplex or trimethylsilyl trifluoromethanesulfonate is preferred. As theinert solvent, dichloromethane, dichloroethane, chloroform, acetonitrileor propionitrile is preferred. The reaction temperature is -78° C. to 0°C. The reaction time is 15 to 60 minutes. The amount of thetrichloroacetimidoyl derivative (IV) to be used is 1.0 to 1.2equivalents based on the hydroquinone derivative (II) either hydroxyl ofwhich is protected.

After completion of the reaction, the reaction mixture is subjected tosolvent extraction and per se known separation and purification methodssuch as chromatography, recrystallization and the like to obtain the 1-or 4-glycosyl derivative in any desired purity. Alternatively, thereaction mixture can be subjected to deprotection without suchseparation and purification.

The sulfo derivative of the hydroquinone of the above formula (I) of thepresent invention can be obtained by reacting the synthetic intermediateof the formula (II) with a reactive derivative of sulfuric anhydride,for example. When R³ of the synthetic intermediate of the formula (II)is a protecting group, this reaction is carried out after desilylation.

Examples of the above reactive derivative of sulfuric anhydride includecomplexes such as sulfur trioxide-pyridine, sulfur trioxide-dioxane,sulfur trioxide-trimethylamine, sulfur trioxide-dimethylformamide or thelike. In addition, sulfuric anhydride, sulfuric-chlorosulfonic acid canalso be used.

As the solvent in this reaction, an inert solvent is preferably used.Examples thereof include dioxane, tetrahydrofuran, chloroform,dichloromethane, pyridine, dimethylformamide and the like.

The amount of the reactive derivative of sulfuric anhydride to be usedis preferably 1.0 to 5.0 mole per 1 mole of the correspondinghydroquinone derivative. In this case, the reaction temperature ispreferably 0° C. to 40° C.

After completion of the reaction, the reaction mixture is subjected tosolvent extraction and per se known separation and purification methodssuch as chromatography, recrystallization and the like to obtain the 1-or 4-sulfate (salt) in any desired purity. Alternatively, the reactionmixture can be subjected to deprotection without such separation andpurification.

The phosphono derivative of the formula (I) can be obtained by reactingthe synthetic intermediate of the formula (II) with an appropriatephosphorylating agent. When R³ of the synthetic intermediate of theformula (II) is a protecting group, the reaction is carried out afterdesilylation.

Examples of the phosphorylating agent to be used in the above reactioninclude orthophosphoric anhydride, metaphosphoric acid,phosphorus.pentachloride, phosphorus oxychloride, pyrophosphoryltetrachloride, tetra-p-nitrophenylpyrophosphoric acid,dimorpholylphosphoryl bromide, o-phenylene phosphoryl chloride,diphenylphosphoryl chloride, di-p-nitrobenzylphosphoryl chloride and thelike. The phosphorylating agent can be used alone or in combination withabout 1 to 5 equivalents of a base in a solvent.

Examples of the base include organic bases such as pyridine,2,6-lutidine, picoline, triethylamine, N-methylmorpholine or the like;inorganic bases such as sodium hydroxide, potassium hydroxide, sodiumbicarbonate, sodium carbonate or the like; and the like.

Examples of the solvent include water, acetone, acetonitrile, dioxane,N,N-dimethylformamide, tetrahydrofuran, dichloromethane and the like.These solvents can be used alone or in combination thereof.

The amount of the phosphorylating agent to be used is preferably 1.0 to5.0 mol per 1 mol of the corresponding hydroquinone derivative. Thereaction temperature is preferably -20 ° C. to 40° C.

After completion of the reaction, the reaction mixture is subjected tosolvent extraction and per se known separation and purification methodssuch as chromtography, recrystallization and the like to obtain the 1-or 4-phosphate (salt) in any desired purity. Alternatively, the reactionmixture can be subjected to deprotection without such separation andpurification.

The hydroquinone derivative thus obtained can be subjected todeprotection, if necessary.

When the hydroquinone has tert-butyldiphenylsilyloxy at the 4-position,the silyl group can be removed by per se known methods such as (1)reaction with tetra-n-butylammonium fluoride in tetrahydrofuran orreaction in acetic acid-water (J. Am. Chem. Soc., 94, 6190 (1972)), (2)reaction with hydrofluoric acid in anhydrous acetonitrile (TetrahedronLett., 1979, 3981), (3) reaction with N-bromosuccinimide in dimethylsulfoxide (Synthesis, 1980, 234), (4) reaction with lithiumtetrafluoroborate (Tetrahedron Lett., 21, 35 (1980)), (5) reaction withan aqueous solution of hydrogen chloride (Tetrahedron Lett., 24, 3251(1983)) or the like. Alternatively, the removal can be carried out underconditions for the hydrolysis of ester and acyl groups used in thepresent invention. Namely, the silyl group, ester group and acyl groupcan be removed simultaneously by reaction with excess 2N-sodiumhydroxide solution in a mixed solvent of water-methanoltetrahydrofuranat room temperature for 15 hours.

When the hydroxyl group at the 1-position of the hydroquinone isprotected by R³ which is lower aliphatic acyl or aromatic acyl such asacetyl or benzoyl, R³ can be removed by alkaline hydrolysis according toconventional methods. When R³ is methoxymethyl, methoxyethoxymethyl,methylthiomethyl or the like which forms a ether bond, it can be removedby per se known methods such as hydrochloric acid-tetrahydrofuran method(Tetrahedron Lett., 1976, 809), zinc bromide or titanium tetrachloridemethod (Tetrahedron Lett., 1976, 809), the method using Hg⁺⁺ or Ag⁺⁺(Tetrahedron Lett., 1975, 3269), bromodimethylborane orbromodiphenylborane method (Tetrahedron Lett., 24, 3969 (1983)) or thelike.

When either A or B of the compound of the formula (I) is protectedphosphono, the deprotection can be carried out by per se known methodssuch as hydrolysis with an acid, catalytic reduction or the like. Wheneither A or B of the compound of the formula (I) is O-acylated and/oresterified glycosyl, it can be removed by conventional methods such asalkaline hydrolysis or the like.

When the compound (I) thus obtained is in the form of a salt, it can beconverted to its free acid, if necessary. When it is a free acid, it canbe converted to its salt by adding a base.

Further, the desired compound (I) can be separated and purified by knownmethods such as extraction, concentration, crystallization,recrystallization, chromatography and the like.

The compound (I) of the present invention itself has various biologicalactivities against animals, particularly mammals (e.g., mouse, rat,guinea pig, dog, rabbit, human, etc.) based mainly on inhibitoryactivity of fatty acid peroxide formation such as hypotensive activity,antiallergic activity, antiulcer activity, antiinflammatory activity,analgesic activity, antiasthmatic activity, immunomodulatory activity,diuretic activity, platelet aggregation inhibitory activity,ameliorative activity of brain and circulatory organs and the like. Thecompound (I) are useful as medicaments such as hypotensive agents,analgesics, antiulcer agents, antiinflammatory agents, diuretics,antiallergic agents, immunomodulators, antithrombogenic agents,ameliorative agents for brain and circulatory organs and the like fortreatment or prevention of, for example, hypertension, cerebralthrombosis, ischemic cardiac infarction, coronary vascular disorders,incontinence of regulation of prostaglandin or thromboxane biosynthesis,immunodeficiency, atherosclerosis, allergosis, bronchial asthma and thelike.

The compounds of the present invention have low toxicity, and can safelybe administered orally or parenterally as it is or in combination with aper se known pharmacologically acceptable carrier or excipient as apharmaceutical composition (e.g., tablets, capsules including softcapsules and microcapsules, liquids and solutions, injections,suppositories, etc.). The dose varies depending upon the subject to betreated, administration route, conditions to be treated. For example,when administered orally to an adult patient with hypertension orbronchial asthma, normally, the compound is preferably administered in aunit dose of about 0.2 mg/kg to about 25 mg/kg body weight 1 to 3 timesa day. For a serious patient who is impossible to treat by oraladministration, parenteral administration of the water-solublederivative of the compound (I) of the present invention is especiallyeffective.

The raw materials in the present invention, namely2,3-dimethoxy-6-(10-hydroxydecyl)-5-methyl-1,4-benzoquinone,6-(12-hydroxydodeca-5,10-diyn-1-yl)-2,3,5-trimethyl-1,4-benzoquinone,6-(11-carboxyundeca-5,10-diyn-1-yl)-2,3,5-trimethyl-1,4-benzoquinone and6-(3-pyridylmethyl)-2,3,5-trimethyl-1,4-benzoquinone can be prepared,for example, according to the methods described in JP-B 1-37384, JP-A57-109739, JP-B 3-2133, JP-A 63-45257 or the like.

As described above, according to the present invention, there areprovided novel compounds wherein the hydroxyl at the 4-position of thehydroquinone derivative is protected regio-selectively. Further, byusing these compounds as intermediates for the production, there areprovided novel hydroquinone derivatives useful as medicaments whereinany desired hydroxyl is chemically modified, regio-selectively.

The following reference examples and examples further illustrate thepresent invention in detail but are not to be construed to limit thescope thereof. In the number of the examples, the symbol "A" representsthe production of the compounds of the above formula (I) and the symbol"B" represents the production of the compounds of the above formula(II).

REFERENCE EXAMPLE 16-(10-Acetoxydecyl)-2,3-dimethoxy-5-methylhydroquinone

2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-1,4-benzoquinone (3.38 g) wasdissolved in dichloromethane (50 ml). Pyridine (1 ml) was added, andacetyl chloride (0.8 ml) was added with stirring under ice-cooling.After stirring for 1 hour at the same temperature, the mixture waswashed with 0.1N hydrochloric acid (50 ml) followed by water (50 ml).The dichloromethane layer was concentrated under reduced pressure toobtain 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as ared oil. This oil was dissolved in ether (50 ml), and a solution ofsodium hydrosulfite (4 g) in water (50 ml) was added. Stirring wascontinued at room temperature until the red color of the ether layerdisappeared. The ether layer was separated, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to obtain thedesired compound (3.8 g) as a pale yellow oil.

EXAMPLE B-16-(10-Acetoxydecyl)-4-tert-butyldipheylsilyloxy-2,3-dimethoxy-5-methylphenol

6-(10-Acetoxydecyl)-2,3-dimethoxy-5-methylhydroquinone (38.0 g) andtert-butylchlorodiphenylsilane (55.0 g) were dissolved indichloromethane (50 ml). Imidazole (13.6 g) was added under a stream ofnitrogen at room temperature. The mixture was stirred at 43° C. for 16hours. The reaction mixture was washed with water (50 ml) andconcentrated under reduced pressure. The residue was subjected to columnchromatography on silica gel and eluted with hexane/ethyl acetate (7:3)to obtain the desired compound (58.0 g).

NMR (CDCl₃) δ (ppm): 1.05 (9H, s), 1.30 (16H, br.s), 2.04 (3H, s), 2.27(3H, s), 2.60 (2H, t, J=7.90Hz), 2.91 (3H, s), 3.47 (3H, s), 4.05 (2H,t, J=6.6Hz), 5.30 (1H, s), 7.30-7.75 (10H, m).

IR (neat) ν: 3540, 2925, 2860, 1740, 1465, 1430, 380, 1260, 1240, 1190,1115, 970, 820, 705, 610 cm⁻¹.

REFERENCE EXAMPLE 2 Methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranuronate

60% Oily sodium hydride (0,366 g) was added to an ice-cooled solution ofmethyl 2,3,4-tri-O-acetyl-D-glucopyranuronate (3.96 g),trichloroacetonitrile (12 ml) and dichloromethane (100 ml), and themixture was stirred at room temperature for 15 minutes. The reactionmixture was subjected to short column (70φ×50 mm) chromatography onsilica gel and eluted with ethyl acetate/hexane (1:1). The eluate wasconcentrated under reduced pressure to obtain the desired compound (4.37g) as crystals (mp: 108° C.).

EXAMPLE A-1 Methyl1-O-[6-(10-acetoxydecyl)-4-hydroxy-2,3-dimethoxy-5-methylphenyl]-2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate

6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol(0.62 g) and methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranuronate (0.82g) were dissolved in dichloromethane (10 ml), and the solution wascooled to -10° C. Boron trifluoride diethyl ether (0.2 ml) was addedwith stirring. The mixture was stirred under ice-cooling for 30 minutesfollowed by addition of water (10 ml) containing sodium bicarbonate (1g) and stirring. The dichloromethane layer was separated andconcentrated under reduced pressure to obtain crude methyl1-O-[6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenyl]-2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate.

The crude product thus obtained was dissolved in tetrahydrofuran (10ml), and tetrabutylammonium fluoride trihydrate (0.2 g) was added. Themixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated under reduced pressure, and the residue wassubjected to column chromatography on silica gel and eluted with ethylacetate/hexane (1:1) to obtain the desired compound (0.36 g).

NMR (CDCl₃) δ (ppm): 1.30 (16H, br.s), 2.02 (3H, s), 2.05 (3H, s), 2.10(3H,s), 2.11 (3H, s), 2.14 (3H, s), 3.69 (3H, s), 3.79 (3H, s), 3.92(3H, s), 4.06 (2H, t, J=6.6Hz), 5.63 (1H, s).

EXAMPLE A-2 Sodium1-O-[4-hydroxy-6-(10-hydroxydecyl)-2,3-dimethoxy-5-methylphenyl]-β-D-glucopyranosiduronateMETHOD 1

6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol(0.62 g) and methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranuronate (0.82g) were dissolved in dichloromethane (10 ml), and the solution wascooled to -10° C. Boron trifluoride diethyl ether (0.2 ml) was addedwith stirring. The mixture was stirred under ice-cooling for 30 minutesfollowed by addition water (10 ml) containing sodium bicarbonate (1 g)and stirring. The dichloromethane layer was separated and concentratedunder reduced pressure to obtain crude methyl1-O-[6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenyl]-2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate.

The crude product thus obtained was dissolved in tetrahydrofuran (10ml), and tetrabutylammonium fluoride trihydrate (0.2 g) was added. Themixture was stirred at room temperature for 2 hours. After concentrationunder reduced pressure, the residue was dissolved in methanol (10 ml). Asolution of sodium hydroxide (1N, 10 ml) was added under ice-cooling,and the mixture was allowed to react at room temperature for 15 hours.The reaction mixture was extracted with ether (20 ml), and the aqueouslayer was concentrated under reduced pressure. The residue was subjectedto Sephadex (trade mark) LH-20 column chromatography and eluted withwater. The desired fraction was lyophilized to obtain the desiredcompound (0.47 g).

METHOD 2

6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol(0.62 g) and methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranuronate (0.82g) were dissolved in dichloromethane (10 ml), and the solution wascooled to -10° C. Boron trifluoride diethyl ether (0.2 ml) was addedwith stirring. The mixture was stirred under ice-cooling for 30 minutesfollowed by addition of water (10 ml) containing sodium bicarbonate (1g) and stirring. The dichloromethane layer was separated andconcentrated under reduced pressure to obtain crude methyl1-O-[6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenyl]-2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate.

To the crude product thus obtained was added methanol (30 ml),tetrahydrofuran (10 ml) and 1N sodium hydroxide solution (15 ml). Themixture was stirred at room temperature for 24 hours. Afterconcentration under reduced pressure, the residue was extracted withether (20 ml). The aqueous layer was concentrated. The residue wassubjected to Sephadex (trade mark) LH-20 column chromatography andeluted with water. The desired fraction was lyophilized to obtain thedesired compound (0.50 g).

mp: 219°-221° C.

Elemental Analysis for C₂₅ H_(39O) ₁₁ Na.0.5H₂ O Calcd.: C,54.84; H,7.36Found: C,54.95; H,7.09

NMR (D₂ O) δ (ppm): 1.15-1.55 (16H, m), 2.08 (3H, s), 2.65 (2H, m), 3.53(2H, t, J=6.76Hz), 3.82 (3H, s), 3.87 (3H, s), 4.86 (1H, d, J=7.09Hz).

UV λmax^(H20) 200 nm E₁ cm (1%)=848,279 nm E₁ cm (1%)=30.

IR (KBr) ν: 1610, 1460, 1420, 1300, 1100, 1050 cm⁻¹.

EXAMPLE A-3

Sodium1-O-[2,3-dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl]-β-D-glucopyranosiduronate

2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-1,4-benzoquinone (338 mg, 1mmol) was dissolved in dichloromethane (5 ml). Pyridine (0.1 ml, 1.2mmol) followed by acetyl chlorides(0.08 ml, 1.1 mmol) was added withstirring under ice-cooling. The mixture was stirred at the sametemperature for 1 hour. Water (5 ml) was added to the reaction mixturewhich was then stirred at room temperature for 20 minutes. Then sodiumhydrosulfite (400 mg, 2.3 mmol) was added, and the mixture was stirredfor 2 hours. The dichloromethane layer was separated, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (5 ml), andtert-butylchlorodiphenylsilane (550 mg, 2 mmol) was added. Thenimidazole (136 mg, 2 mmol) was added under a stream of nitrogen. Afterstirring at 43° C. for 16 hours, the mixture was washed with water (5ml), and the organic layer was dried over anhydrous magnesium sulfate.Concentration under reduced pressure gave crude6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol.The crude product was dissolved in dichloromethane (10 ml) followed byaddition of methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranuronate (2.1mmol), and the mixture was ice-cooled. Boron trifluoride diethyl ether(0.2 ml) was added, and the mixture was stirred at the same temperaturefor 30 minutes. Then water (10 ml) containing sodium bicarbonate (1 g)was added, and the mixture was stirred for 5 minutes. Thedichloromethane layer was separated and concentrated under reducedpressure. To the residue were added tetrahydrofuran (15 ml), methanol(10 ml) and 1N sodium hydroxide solution (20 ml), and the mixture wasallowed to react at room temperature for 40 hours. The solvent wasdistilled off under reduced pressure, and the residue was extracted withether (20 ml). Then the aqueous layer was subjected to Sephadex (trademark) LH-20 column chromatography and eluted with water. The desiredfraction was lyophilized to obtain the desired compound (290 mg).

EXAMPLE A-4 Sodium1-O-[4-hydroxy-6-(12-hydroxydodeca-5,10-diyn-1-yl)-2,3,5-trimethylphenyl-.beta.-D-glucopyranosiduronate

6-(12-Hydroxydodeca-5,10-diyn-1-yl)-2,3,5-trimethyl-1,4-benzoquinone(326 mg, 1 mmol) was treated according to the same manner as thatdescribed in Example A-3 to obtain the desired compound (310 mg).

Elemental Analysis for C₂₇ H₃₅ O₉ Na.H₂ O Calcd.: C,59.55; H,6.85 Found:C,59.40; H,6.55

NMR (D₂ O) δ (ppm): 1.542 (4H, m), 1.651 (2H, quintet, J=7.0Hz ), 2.150(3H, s), 2.214 (3H, s), 2.234 (3H, s), 2.260-2.350 (6H, m), 2.74 (2H,m), 2.85 (2H, m), 3.492 (1H,d, J=9.50Hz), 3.590 (2H, m), 3.680 (1H, dd,J=7.80,9.50Hz), 4,171 (2H, t, J=2.20Hz), 4.690 (1H, d, J=7.80Hz).

IR (KBr) ν: 3380, 1600 cm⁻¹.

SIMS (H₂ O+Glycerol): 527 (M+1), 549 (M+Na)

SIMS (H₂ O+Glycerol+0.1NKJ): 527 (M+1), 543 (M-Na+K+1), 565 (M+K), 581(M-Na+K+K).

EXAMPLE B-21-Acetoxy-6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylbenzene

6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol(0.65 g) was dissolved in dichloromethane (5 ml), and triethylamine (0.2ml) followed by acetyl chloride (0.08 g) was added. The mixture wasstirred at the same temperature for 30 minutes. The reaction mixture wasconcentrated, and then the residue was subjected to columnchromatography on silica gel and eluted with hexane/ethyl acetate (9:1)to obtain the desired compound (0.483 g).

NMR (CDCl₃) δ (ppm): 1.05 (9H, s), 1.31 (16H, s), 2.05 (3H, s), 2.29(3H, s), 2.31 (3H, s), 2.45 (2H, t, J=7.90Hz), 2.87 (3H, s), 3.40 (3H,s), 4.06 (2H, t, J=6.6Hz), 7.35-7.70 (10H, m).

IR (neat) ν: 2925, 2850, 1770, 1760, 1470, 1420, 1360, 1240, 1200, 1110,1060, 1020, 960 cm⁻¹.

EXAMPLE A-51-Acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-4-hydroxy-5-methylbenzene

1-Acetoxy-6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylbenzene(0.483 g) was dissolved in tetrahydrofuran (5 ml), andtetrabutylammonium fluoride trihydrate (0.5 g) was added. The mixturewas stirred at room temperature for 30 minutes. After concentrationunder reduced pressure, the residue was subjected to columnchromatography on silica gel and eluted with hexane/ethyl acetate (7:3)to obtain the desired compound (0.24 g).

NMR (CDCl₃) δ (ppm): 1.29-1.60 (16H,s), 2.05 (3H,s) , 2.16 (3H, s), 2.33(3H, s), 2.43 (2H, t, J=7.90Hz), 3.83 (3H, s), 3.91 (3H, s), 4.06 (2H,t, J=6.60 Hz), 5.73 (1H, s).

IR (neat) ν: 3450, 2925, 2850, 1760, 1740, 1490, 1465, 1425, 1380, 1365,1240, 1210, 1110, 1050 cm⁻¹.

EXAMPLE A-6 Sodium1-O-[2,3-dimethoxy-1-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl]-β-D-glucopyranosiduronate

1-Acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-4-hydroxy-5-methylbenzene(0.9 g) and methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranosiduronate(1.3 g) were dissolved in dichloromethane (20 ml). Boron trifluoridediethyl ether (0.4 ml) was added with stirring under ice-cooling, andthe mixture was stirred at the same temperature for 30 minutes. Thenwater (20 ml) containing sodium bicarbonate (1 g) was added, and themixture was stirred for 10 minutes. The dichloromethane layer wasseparated and concentrated under reduced pressure to obtain crude methyl1-O-[1-acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-5-methylphenyl]-2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate.This was dissolved in methanol (20 ml), and 1N sodium hydroxide solution(20 ml) was added under ice-cooling. The mixture was allowed to react atroom temperature for 16 hours. The methanol was distilled off underreduced pressure, and the residue was subjected to Sephadex (trade mark)LH-20 column chromatography and eluted with water. The desired fractionwas lyophilized to obtain the desired compound (0.88 g). This compoundwas dissolved in a small amount of methanol for crystallization toobtain crystals (0.68 g).

mp. 210°-211° C.

Elemental Analysis for C₂₅ H₃₉ O₁₁ Na Calcd.: C,55.75; H,7.30 Found:C,55.48; H,7.29

NMR (D₂ O) δ (ppm): 1.15-1.55 (16H, m), 2.20 (3H, s), 2.55 (2H, s), 3.53(2H, t, J=6.76Hz), 3.81 (3H, s), 3.86 (3H, s), 4.78 (1H, d, J=7.58Hz).

IR (KBr) ν: 1610, 1460, 1425, 1370, 1300, 1090, 1060 cm⁻¹.

UV λmax^(H20) 200 nm, E₁ cm (1%)=803,279 nm, E₁ cm (1%)=28.

[α]_(D) ²⁴ =-29.8° (c=0.215, H₂ O).

EXAMPLE A-7

Sodium1-O-[2,3-dimethoxy-1-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl]-β-D-glucopyranosiduronate

2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-1,4-benzoquinone (338 mg, 1mmol) was dissolved in dichloromethane (5 ml). Pyridine (0.1 ml, 1.2mmol) followed by acetyl chloride (0.08 ml, 1.1 mmol) was added withstirring under ice-cooling. The mixture was stirred at the sametemperature for 1 hour. Water (5 ml) was added to the reaction mixturewhich was then stirred at room temperature for 20 minutes. Then sodiumhydrosulfite (400 mg, 2.3 mmol) was added, and the mixture was stirredfor 2 hours. The dichloromethane layer was separated, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (5 ml), andtert-butylchlorodiphenylsilane (550 mg, 2 mmol) was added. Thenimidazole (136 mg, 2 mmol) was added under a stream of nitrogen. Thereaction mixture was stirred at 43° C. for 16 hours and then washed withwater (5 ml), and the organic layer was dried over anhydrous magnesiumsulfate. Concentration under reduced pressure gave crude6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol.The crude product was dissolved in dichloromethane (5 ml), and pyridine(0.1 ml, 1.2 mmol) followed by acetyl chloride (0.08 ml, 1.1 mmol) wasadded. The mixture was stirred at the same temperature for 30 minutesand washed with water (5 ml), and the dichloromethane layer wasconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (8 ml), and tetrabutylammonium fluoride trihydrate (731mg, 2 mmol) was added. The mixture was stirred at room temperature for30 minutes. The reaction mixture was concentrated under reducedpressure, and the residue was dissolved in ether and washed with water.The ether layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain crude1-acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-4-hydroxy-5-methylbenzene.This crude product was dissolved in dichloromethane (10 ml). Methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranosiduronate(1.4 g, 3 mmol) was added, and the mixture was ice-cooled. Borontrifluoride diethyl ether (0.2 ml) was added, and the mixture wasstirred at the same temperature for 30 minutes. Then water (10 ml)containing sodium bicarbonate (1 g) was added, and the mixture wasstirred for 5 minutes. The dichloromethane layer was separated andconcentrated under reduced pressure to obtain crude methyl1-O-[1-acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-5-methylphenyl]-2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate.This crude product was dissolved in methanol (10 ml), and 1N sodiumhydroxide solution (10 ml) was added. The mixture was allowed to reactat room temperature for 16 hours and concentrated under reducedpressure. The residue was extracted with ether and then subjected toSephadex (trade mark) LH-20 column chromatography and eluted with water.The desired fraction was lyophilized to obtain the desired compound (270mg).

EXAMPLE A-8

Sodium1-O-[1-hydroxy-6-(12-hydroxydodeca-5,10-diyn-1-yl)-2,3,5-trimethylphenyl]-β-D-glucopyranosiduronate

1-Hydroxy-6-(12-hydroxydodeca-5,10-diyn-1-yl)-2,3,5-trimethyl-1,4-benzoquinone(326 mg, 1 mmol) was treated according to the same manner as thatdescribed in Example A-6 to obtain the desired compound (290 mg).

Elemental Analysis for C₂₇ H₃₅ O₉ Na.1.5H₂ O Calcd.: C,58.58; H,6.92Found: C,58.87; H,6.73

NMR (D₂ O) δ (ppm): 1.561 (4H, m), 1.649 (2H, quintet, J=7.0Hz), 2.150(3H, s), 2.228 (3H, s), 2.283 (3H, s), 2.230 (2H), 2.280 (2H), 2.325(2H, tt), 2.667 (2H, br.t), 3.502 (1H, d, J=9.5Hz), 3.580 (2H, m), 3.693(1H, dd, J=7.8,9.5Hz), 4.162 (2H, t, J=2.1Hz), 4.677 (1H, d, J=7.8Hz).

IR (KBr) ν: 3380, 1600 cm⁻¹.

SIMS (H₂ O+Glycerol): 527 (M+1), 549 (M+Na)

SIMS (H₂ O+Glycerol+0.1NKJ): 527 (M+1), 543 (M-Na+K+1), 565 (M+K), 581(M-Na+K+K).

EXAMPLE A-9 Sodium1-O-[4-hydroxy-6-(3-pyridylmethyl)-2,3,5-trimethylphenyl]-β-D-glucopyranosiduronate

6-(3-Pyridylmethyl)-2,3,5-trimethyl-1,4-benzoquinone (241 mg, 1 mmol)was dissolved in dichloromethane (5 ml). The solution was stirred for 1hour with a solution containing sodium hydrosulfite (400 mg, 2.3 mmol)in water (5 ml). The dichloromethane layer was separated, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (5 ml), andtert-butylchlorodiphenylsilane (550 mg, 2 mmol) was added. Thenimidazole (136 mg, 2 mmol) was added under a stream of nitrogen. Thereaction mixture was stirred at 43° C. for 16 hours and washed withwater (5 ml). The organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to obtain crude4-tert-butyldiphenylsilyloxy-6-(3-pyridylmethyl)-2,3,5-trimethylphenol.This crude product was dissolved in dichloromethane (10 ml), and methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranosiduronate (1g, 2.1 mmol) was added. Boron trifluoride diethyl ether (0.2 ml) wasadded under ice-cooling, and the mixture was stirred at the sametemperature for 30 minutes. Then water (10 ml) containing sodiumbicarbonate (1 g) was added, and the mixture was stirred for 5 minutes.The dichloromethane layer was separated and concentrated under reducedpressure. To the residue were added tetrahydrofuran (15 ml), methanol(10 ml) and 1N sodium hydroxide solution (20 ml), and the mixture wasallowed to react at room temperature for 40 hours and concentrated underreduced pressure. The residue was extracted with ether, and the aqueouslayer was subjected to Sephadex (trade mark) LH-20 column chromatographyand eluted with water. The desired fraction was lyophilized to obtainthe desired compound (210 mg) as white powder.

mp: 215° C. (dec.)

Elemental Analysis for C₂₁ H₂₄ NO₈ Na.2H₂ O Calcd.: C,52.83; H,5.91;N,2.93 Found: C,52.76; H,5.89; N,2.88

NMR (D₂ O) δ (ppm): 2.006 (3H, s), 2.171 (3H, s), 2.275 (3H, s),3.400-3.682 (4H, m), 4.288 (2H, ABq, J=16,41Hz), 4.694 (1H, d, J=8Hz),7.340-8.314 (4H, m).

IR (KBr) ν: 3380, 1610 cm⁻¹.

[α]_(D) ²³ =-35.5° (c=0.95, H₂ O).

EXAMPLE A-10 Sodium1-O-[1-hydroxy-6-(3-pyridylmethyl)-2,3,5-trimethylphenyl]-β-D-glucopyranosiduronate

6-(3-Pyridylmethyl)-2,3,5-trimethyl-1,4-benzoquinone (241 mg, 1 mmol)was dissolved in dichloromethane (5 ml). The solution was stirred for 1hour with a solution containing sodium hydrosulfite (400 mg, 2.3 mmol)in water (5 ml). The dichloromethane layer was separated, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (5 ml), andtert-butylchlorodiphenylsilane (550 mg, 2 mmol) was added. Thenimidazole (136 mg, 2 mmol) was added under a stream of nitrogen. Thereaction mixture was stirred at 43° C. for 16 hours and washed withwater (5 ml). The organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to obtain crude4-tert-butyldiphenylsilyloxy-6-(3-pyridylmethyl)-2,3,5-trimethylphenol.

This crude product was dissolved in dichloromethane (5 ml), and pyridine(0.1 ml, 1.2 mmol) followed by acetyl chloride (0.08 ml, 1.1 mmol) wasadded with stirring under ice-cooling. The mixture was stirred at thesame temperature for 30 minutes and washed with water (5 ml). Thedichloromethane layer was concentrated under reduced pressure. Theresidue was dissolved in tetrahydrofuran (8 ml), and tetrabutylammoniumfluoride trihydrate (731 mg, 2 mmol) was added. The mixture was stirredat room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved inether and washed with water. The ether layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to obtaincrude 1-acetoxy-4-hydroxy-6-(3-pyridylmethyl)-2,3,5-trimethylbenzene.This crude product was dissolved in dichloromethane (10 ml). Methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranuronate (1.4g, 3 mmol) was added, and boron trifluoride diethyl ether (0.2 ml) wasadded under ice-cooling. The mixture was stirred at the same temperaturefor 30 minutes. Then water (10 ml) containing sodium bicarbonate (1 g)was added, and the mixture was stirred for 5 minutes. Thedichloromethane layer was separated and concentrated under reducedpressure to obtain crude methyl1-O-[1-acetoxy-6-(3-pyridylmethyl)-2,3,5-trimethylphenyl]-2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate.This crude product was dissolved in methanol (10 ml), and 1N sodiumhydroxide solution (10 ml) was added. The mixture was allowed to reactat room temperature for 16 hours and concentrated under reducedpressure. The residue was extracted with ether, and the aqueous layerwas subjected to Sephadex (trade mark) LH-20 column chromatography andeluted with water. The desired fraction was lyophilized to obtain thedesired compound (200 mg).

mp: 210° C. (dec.)

Elemental Analysis for C₂₁ H₂₄ NO₈ Na.1.5H₂ O Calcd.: C,53.85; H,5.81;N,2.99 Found : C,54.12; H,6.07: N,2.95

NMR (D₂ O) δ (ppm): 2.155 (3H, s), 2.208 (3H, s), 2.261 (3H, s),3.473-3.750 (4H, m), 4. 073 (2H, s), 4.679 (1H, d, J=8Hz), 7.290-8.326(4H, m).

IR (KBr) ν: 3410, 1610, 1055 cm⁻¹.

REFERENCE EXAMPLE 3 Disodium1-O-[6-(11-carboxyundeca-5,10-diyn-1-yl)-4-hydroxy-2,3,5-trimethylphenyl]-β-D-glucopyranosiduronate

6-(11-Carboxyundeca-5,10-diyn-1-yl)-2,3,5-trimethyl-1,4-benzoquinone(340 mg, 1 mmol) was dissolved in ether (10 ml). A solution ofdiazomethane in ether was added under ice-cooling formethyl-esterification. Nitrogen gas was introduced to remove excessdiazomethane. Then water (5 ml) containing sodium hydrosulfite (400 mg,2.3 mmol) was added, and the mixture was stirred for 1 hour. The etherlayer was separated, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved indichloromethane (5 ml), and tert-butylchlorodiphenylsilane (550 mg, 2mmol) was added. Then imidazole (136 mg, 2 mmol) was added under astream of nitrogen, and the mixture was stirred at 43° C. for 16 hours.The reaction mixture was washed with water (5 ml), and the organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to obtain crude4-tert-butyldiphenylsilyloxy-6-(11-methoxycarbonylundeca-5,10-diyn-1-yl)-2,3,5-trimethylphenol.This crude product was dissolved in dichloromethane (10 ml), and methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranosiduronate (1g, 2.1 mmol) was added. Boron trifluoride diethyl ether (0.2 ml) wasadded under reduced pressure, and the mixture was stirred at the sametemperature for 30 minutes. Then water (10 ml) containing sodiumbicarbonate (1 g) was added, and the mixture was stirred for 5 minutes.The dichloromethane layer was separated and concentrated under reducedpressure. To the residue were added tetrahydrofuran (15 ml), methanol(10 ml) and 1N sodium hydroxide solution (20 ml), and the mixture wasallowed to react at room temperature for 40 hours and concentrated underreduced pressure. The residue was extracted with ether and the aqueouslayer was subjected to Sephadex (trade mark) LH-20 column chromatographyand eluted with water. The desired fraction was lyophilized to obtainthe desired compound (290 mg) as white powder.

Elemental Analysis for C₂₇ H₃₂ O₁₀ Na₂.2.5H₂ O Calcd.: C,53.38; H,6.14Found: C,53.40; H,6.34

NMR (D₂ O) δ (ppm): 1.54 (4H, m), 1.69 (2H, quintet), 2.15 (3H, s), 2.21(3H, s), 2.23 (3H, s), 2.25-2.30 (4H, m) , 2.38 (2H, t), 2.74-2.84 (2H,m), 3.49 (1H, d), 3.59 (2H, m), 3.68 (1H, t), 4.69 (1H, d, J=7.6Hz).

IR (KBr): ν: 3400, 2230, 1580 cm⁻¹.

SIMS (H₂ O+Glycerol): 563 (M+1), 585 (M+Na).

SIMS (H₂ O+Glycerol+0.1NKJ): 563 (M+1), 579 (M-Na+K+1), 585 (M+Na), 601(M+K).

REFERENCE EXAMPLE 4 Disodium1-O-[6-(11-carboxyundeca-5,10-diyn-1-yl)-1-hydroxy-2,3,5-trimethylphenyl]-β-D-glucopyranosiduronate

6-(11-Carboxyundeca-5,10-diyn-1-yl)-2,3,5-trimethyl-1,4-benzoquinone(340 mg, 1 mmol) was dissolved in ether (10 ml). A solution ofdiazomethane in ether was added under ice-cooling formethyl-esterification. Nitrogen gas was introduced to remove excessdiazomethane. Then water (5 ml) containing sodium hydrosulfite (400 mg,2.3 mmol) was added, and the mixture was stirred for 1 hour. The etherlayer was separated, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved indichloromethane (5 ml), and tert-butylchlorodiphenylsilane (550 mg, 2mmol) was added. Then imidazole (136 mg, 2 mmol) was added under astream of nitrogen, and the mixture was stirred at 43° C. for 16 hours.The reaction mixture was washed with water (5 ml), and the organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to obtain crude4-tert-butyldiphenylsilyloxy-6-(11-methoxycarbonylundeca-5,10-diyn-1-yl)-2,3,5-trimethylphenol.This crude product was dissolved in dichloromethane (5 ml), and pyridine(0.1 ml, 1.2 mmol) followed by acetyl chloride (0.08 ml, 1.1 mmol) wasadded with stirring under ice-cooling. The mixture was stirred at thesame temperature for 30 minutes and washed with water (5 ml). Thedichloromethane layer was concentrated under reduced pressure. Theresidue was dissolved in tetrahydrofuran (8 ml), and tetrabutylammoniumfluoride trihydrate (731 mg, 2 mmol) was added. The mixture was stirredat room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved inether and washed with water. The ether layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to obtaincrude 1-acetoxy-4-hydroxy-6-(11-methoxycarbonylundeca-5,10-diyn-1-yl)-2,3,5-trimethylbenzene. This crude product was dissolvedin dichloromethane (10 ml). Methyl1-O-trichloroacetimidoyl-2,3,4-tri-O-acetyl-α-D-glucopyranosiduronate(1.4 g, 3 mmol) was added, and boron trifluoride diethyl ether (0.2 ml)was added under ice-cooling. The mixture was stirred at the sametemperature for 30 minutes. Then water (10 ml) containing sodiumbicarbonate (1 g) was added, and the mixture was stirred for 5 minutes.The dichloromethane layer was separated and concentrated under reducedpressure to obtain crude methyl1-O-[1-acetoxy-6-(11-methoxycarbonylundeca-5,10-diyn-1-yl)-2,3,5-trimethylphenyl]-2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate.This crude product was dissolved in methanol (10 ml), and 1N sodiumhydroxide solution (10 ml) was added. The mixture was allowed to reactat room temperature for 16 hours and concentrated under reducedpressure. The residue was extracted with ether, and the aqueous layerwas subjected to Sephadex (trade mark) LH-20 column chromatography andeluted with water. The desired fraction was lyophilized to obtain thedesired compound (265 mg).

Elemental Analysis for C₂₇ H₃₂ O₁₀ Na₂.2.5H₂ O Calcd.: C,53.38; H,6.14Found: C,53.65; H,5.84

NMR (D₂ O) δ (ppm): 1.56 (4H, m), 1.69 (2H, quintet), 2.15 (3H, s), 2.23(3H, s), 2.28 (3H, s), 2.20- 2.30 (4H, m), 2.38 (2H, t), 2.67 (2H,br.t), 3.50 (1H, d), 3.59 (2H, m), 3.69 (1H, t), 4.68 (1H, d, J=7.8Hz).

IR (KBr): ν 3400, 2220, 1580 cm⁻¹.

SIMS (H₂ O+Glycerol): 563 (M+1), 585 (M+Na).

SIMS (H₂ O+Glycerol+0.1NKJ): 563 (M+1), 579 (M-Na+K+1), 585 (M+Na), 601(M+K).

REFERENCE EXAMPLE 5 Sodium2,3-dimethoxy-1-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl-4-sulfate

1-Acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-4-hydroxy-5-methylbenzene(2.1 g) obtained in Example A-5 was dissolved in dimethylformamide (10ml). Sulfur trioxidepyridine complex (1.6 g) was added, and the mixturewas allowed to react at room temperature for 5 hours followed by removalof dimethylformamide under reduced pressure. The residue was dissolvedin methanol (20 ml), and 1N sodium hydroxide solution (25 ml) was added.The mixture was heated at 50 ° C. for 10 minutes. After concentrationunder reduced pressure, the residue was subjected to Amberlite (trademark) XAD-II column chromatography and eluted with water followed by 50%ethanol/water. The desired fraction was concentrated and lyophilized.The desired compound thus obtained was dissolved in a small amount ofmethanol, and 10 fold amount of ethyl acetate was added forcrystallization to obtain crystals (1.4 g).

mp: 146°-147° C. (dec.)

Elemental Analysis for C₁₉ H₃₁ O₈ SNa Calcd.: C,51.57; H,7.06 Found:C,51.26; H,7.03

NMR (D₂ O) δ (ppm): 1.21 (16H, br.s), 2.21 (3H, s), 2.55 (2H, t,J=7.90Hz), 3.54 (2H, t, J=6.60Hz), 3.81 (3H, s), 3.88 (3H, s).

IR (KBr) ν: 1615, 1585, 1485, 1465, 1425, 1365, 1275, 1255, 1120, 1100,1060, 1005, 950, 940, 790, 755, 725, 675, 630, 610 cm⁻¹.

REFERENCE EXAMPLE 6 Sodium2,3-dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl-1-sulfate

6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol(3.10 g) obtained in Example B-1 was dissolved in dimethylformamide (15ml). Sulfur trioxide-pyridine complex (1.6 g) was added, and the mixturewas stirred at room temperature for 5 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was dissolved inmethanol (20 ml), 1N sodium hydroxide solution (25 ml) was added, andthe mixture was stirred at room temperature for 3 days. The solvent wasdistilled off under reduced pressure, and the residue was extracted withether. The aqueous layer was subjected to Amberlite (trade mark) XAD-IIcolumn chromatography and eluted with water followed by 50%ethanol/water. The desired fraction was concentrated and thenlyophilized. The desired compound thus obtained was crystallized frommethanol/ethyl acetate to obtain crystals (1.3 g).

mp: 136°-137° C.

Elemental Analysis for C₁₉ H₃₁ O₈ SNa.0.5H₂ O Calcd.: C,50.54; H,7.14Found: C,50.79; H,7.10

NMR (D₂ O) δ (ppm): 1.10-1.60 (16H, m), 2.11 (3H, s), 2.70 (2H, t,J=7.9Hz), 3.55 (2H, t, J=6.6Hz), 3.82 (3H, s), 3.89 (3H, s).

IR (KBr) ν: 3400, 2925, 2850, 1480, 1460, 1425, 1380, 1365, 1255, 1220,1115, 1095, 1040, 1000, 960, 930, 790, 770, 590 cm⁻¹.

REFERENCE EXAMPLE 7 Sodium2,3-dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl-1-sulfate

2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methylbenzoquinone (3.38 g, 10 mmol)was dissolved in dichloromethane (50 ml). Pyridine (1 ml) followed byacetyl chloride (0.8 ml) was added with stirring under ice-cooling, andthe mixture was stirred for 1 hour. Water (5 ml) was added to thereaction mixture which was then stirred for 20 minutes. Then sodiumhydrosulfite (4 g) was added, and the mixture was stirred at roomtemperature for 2 hours. The dichloromethane layer was separated, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was dissolved in dichloromethane (50 ml), andtert-butylchlorodiphenylsilane (5.5 g, 20 mmol) and imidazole (1.36 g,20 mmol) were added. The mixture was stirred at 43° C. for 16 hoursunder a stream of nitrogen. The reaction mixture was washed with water,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to obtain crude6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol.The concentrate was dissolved in dimethylformamide (15 ml). Sulfurtrioxide-pyridine complex (3.2 g, 20 mmol) was added, and the mixturewas stirred at room temperature for 5 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was dissolved inmethanol (40 ml), and 1N sodium hydroxide solution (60 ml) was added.The mixture was allowed to react for 16 hours. Methanol was distilledoff under reduced pressure, and the residue was extracted with ether.The aqueous layer was subjected to Amberlite (trade mark) XAD-II columnchromatography and eluted with water followed by 50% ethanol/water. Thedesired fraction was concentrated and lyophilized to obtain the desiredcompound (2.8 g).

REFERENCE EXAMPLE 8 Sodium2,3-dimethoxy-1-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl-4-sulfate

2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methylbenzoquinone (3.38 mg, 10mmol) was dissolved in dichloromethane (50 ml). Pyridine (1 ml) followedby acetyl chloride (0.8 ml) was added with stirring under ice-cooling.The mixture was stirred for 1 hour. Water (50 ml) was added to thereaction mixture which was then stirred for 20 minutes. Then sodiumhydrosulfite (4 g) was added, and the mixture was stirred at roomtemperature for 2 hours. The dichloromethane layer was separated, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was dissolved in dichloromethane (50 ml), andtert-butylchlorodiphenylsilane (5.5 g, 20 mmol) and imidazole (1.36 g,20 mmol) were added. The mixture was stirred at 43° C. for 16 hoursunder a stream of nitrogen. The reaction mixture was washed with water,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to obtain crude 6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol. The concentrate wasdissolved in dichloromethane (100 ml). Triethylamine (2 ml) followed byacetyl chloride (0.8 ml) was added, and the mixture was stirred for 30minutes. The reaction mixture was washed with water and concentratedunder reduced pressure. The residue was dissolved in tetrahydrofuran (50ml), and tetrabutylammonium fluoride trihydrate (1.3 g, 50 mmol) wasadded. The mixture was stirred at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was dissolved in dichloromethane, washed with water and thendried over anhydrous magnesium sulfate. The dichloromethane layer wasconcentrated under reduced pressure to obtain crude1-acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-4-hydroxy-5-methylbenzene.This crude product was dissolved in dimethylformamide (15 ml). Sulfurtrioxidepyridine complex (6.4 g, 40 mmol) was added, and the mixture wasallowed to react for 5 hours at room temperature. The reaction mixturewas concentrated under reduced pressure. The residue was dissolved inmethanol (40 mi), 1N sodium hydroxide solution (30 ml) was added, andthe mixture was stirred at room temperature for 16 hours. The reactionmixture was concentrated under reduced pressure, and the residue wasextracted with ether. The aqueous layer was subjected to Amberlite(trade mark) XAD-II column chromatography and eluted with water followedby 50% ethanol/water. The desired fraction was lyophilized to obtain thedesired compound (2.4 g).

EXAMPLE A-11 Sodium4-hydroxy-6-(3-pyridylmethyl)-2,3,5-trimethylphenyl-1-sulfate

6-(3-Pyridylmethyl)-2,3,5-trimethyl-1,4-benzoquinone (2.41 g, 10 mmol)was dissolved in dichloromethane (50 ml). The solution was stirred withwater (50 ml) containing sodium hydrosulfite (4 g) for 2 hours.According to the same manner as that described in Reference Example 7,the mixture was subjected to tertbutyldiphenylsilylation, sulfonationand hydrolysis to obtain the desired compound (2.11 g).

mp: 210°-215° C. (dec.)

Elemental Analysis for C₁₅ H₁₆ NO₅ SNa.0.9H₂ O Calcd.: C,49.83; H,4.96;N,3.87 Found: C,50.03; H,5.01; N,3.91

NMR (D₂) δ (ppm): 2.164 (3H, s), 2.195 (3H, s), 2.259 (3H, s), 4.079(2H, s), 7.318-8,326 (4H, m).

IR (KBr) ν: 3450, 1630, 1245, 1040 cm⁻¹

REFERENCE EXAMPLE 9 Sodium4-hydroxy-6-(12-hydroxydodeca-5,10-diyn-1-yl)-2,3,5-trimethylphenyl-1-sulfate

6-(12-Hydroxydodeca-5,10-diyn-1-yl)-2,3,5-trimethyl-1,4-benzoquinone(3.26 g, 10 mmol) was treated according to the same manner as thatdescribed in Reference Example 7 to obtain the desired compound (3.05g).

Elemental Analysis for C₂₁ H₂₇ O₆ SNa.1.5H₂ O Calcd.: C,55.13; H,6.61Found : C,55.33; H,6.37

NMR (CDCl₃ +CD₃ OD) δ (ppm): 1.35-1.83 (6H, s), 2.12 (3H, s), 2.17 (3H,s), 2.26 (3H, s), 2.00-2.43 (6H, m), 2.86 (2H, m), 4.16 (2H, t, J=2Hz).

IR (KBr) ν: 3440, 1240, 1035 cm⁻¹.

EXAMPLE A-12 Sodium1-hydroxy-6-.(3-pyridylmethyl)-2,3,5-trimethylphenyl-4-sulfate

6-(3-Pyridylmethyl)-2,3,5-trimethyl-1,4 -benzoquinone (2.41 g, 10 mmol)was dissolved in dichloromethane (50 ml). The solution was stirred withwater (50 ml) containing sodium hydrosulfite (4 g) for 2 hours. Thehydroquinone thus obtained was treated according to the same manner asthat described in Reference Example 8 to obtain the desired compound(1.95 g).

mp: 182°-193° C.

Elemental Analysis for C₁₅ H₁₆ NO₅ SNa.1.2H₂ O Calcd.: C,49.10; H,5.05;N,3.82 Found: C,49.12; H,5.12; N,3.84

NMR (D₂ O) 6: 2.054 (3H, s), 2.180 (3H, s), 2.257 (3H, s), 4.254 (2H,s), 7.288-8.300 (4H, m).

IR (KBr) ν: 3440, 1635, 1245, 1030 cm⁻¹.

REFERENCE EXAMPLE 10 Sodium1-hydroxy-6-(12-hydroxydodeca-5,10-diyn-1-yl)-2,3,5-trimethylphenyl-4-sulfate

6-(12-Hydroxydodeca-5,10-diyn-1-yl)-2,3,5-trimethyl-1,4-benzoquinone(3.26 g, 10 mmol) was treated according to the same manner as thatdescribed in Reference Example 8 to obtain the desired compound (2.88g).

Elemental Analysis for C₂₁ H₂₇ O₆ SNa.1.5H₂ O Calcd.: C,55.13; H,6.61Found: C,54.88; H,6.35

NMR (CDCl₃ +CD₃ OD) δ (ppm): 1.35-1.83 (6H, m), 2.12 (3H, s), 2.26 (3H,s), 2.31 (3H, s), 2.00-2.43 (6H, m), 2.62 (2H, m), 4.16 (2H, t, J=2Hz).

IR (KBr) ν: 3460, 1235, 1040 cm⁻¹.

EXAMPLE A-13 Sodium2,3-dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl-1-phosphate

6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol(6 g, 10 mmol) obtained in Example B-1 was dissolved in toluene (50 ml),and phosphorus oxychloride (4.8 ml) was added. Pyridine (1.6 ml) wasadded with stirring under ice-cooling, and then the mixture was stirredat room temperature for 2 hours. The mixture was concentrated underreduced pressure, and ice water (50 ml) and ethyl acetate (50 ml) wereadded to the residue. The organic layer was separated and concentratedunder reduced pressure. The residue was dissolved by addingtetrahydrofuran (30 ml) and methanol (70 ml) thereto. 1N Sodiumhydroxide solution (100 ml) was added under ice-cooling, and then themixture was stirred at room temperature overnight. The solvent wasdistilled off under reduced pressure, acetic acid (6 ml) was added, andthe mixture was extracted with hexane. The aqueous layer was subjectedto Amberlite (trade mark) XAD-II column chromatography and eluted withwater followed by 50% methanol/water. The desired fraction wasconcentrated and lyophilized, and ethanol (2 ml) was added to the powderthus obtained for crystallization. The crystals were separated byfiltration, washed with ethyl acetate followed by hexane to obtain thedesired compound (1.58 g).

mp: 163.7°-165° C.

Elemental Analysis for C₁₉ H₃₂ O₈ PNa Calcd.: C,51.58; H,7.29; P,7.00Found: C,51.33; H.7.46; P,6.75

NMR (D₂ O) δ (ppm): 1.20-1.60 (16H, m), 2.17 (3H, s), 2.67 (2H, m), 3.61(2H, t, J=6.6Hz), 3.88 (3H, s), 3.91 (3H, s).

IR (KBr) ν: 3540, 2925, 2850, 1480, 1470, 1455, 1435, 1380, 1370, 1205,1125, 1100, 1055, 945, 930, 805, 535 cm⁻¹.

EXAMPLE A-14 Sodium2,3-dimethoxy-1-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl-4-phosphate

1-Acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-4-hydroxy-5-methylbenzene(4.2 g, 10 mmol) obtained in Example A-5 was dissolved in toluene (15ml), and phosphorus oxychloride (1.9 ml, 20 mmol) was added. Pyridine(1.6 ml, mmol) was added with stirring under ice-cooling, and then themixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated under reduced pressure, and ice water (50 ml)and ethyl acetate (50 ml) were added to the residue. The organic layerwas separated and concentrated under reduced pressure. Then the residuewas dissolved in tetrahydrofuran (50 ml). 1N Sodium hydroxide solution(100 ml) was added under ice-cooling, and then the mixture was stirredat room temperature for 45 minutes. The mixture was concentrated underreduced pressure, acetic acid (6 ml) was added to the residue, and themixture was extracted with hexane. The aqueous layer was subjected toAmberlite (trade mark) XAD-II column chromatography and eluted withwater followed by 50% methanol/water. The desired fraction wasconcentrated and lyophilized. The white powder thus obtained wasdissolved in methanol and concentrated for crystallization. The crystalswere separated by filtration, washed with ethyl acetate followed byhexane to obtain the desired compound (2.0 g).

mp: 158°-160° C.

Elemental Analysis for C₁₉ H₃₂ O₈ PNa Calcd.: C,51.58; H,7.29; P,7.00Found: C,51.56; H.7.38; P,7.01

NMR (D₂ O) δ (ppm): 1.20-1.60 (16H, m), 2.24 (3H, s), 2.61 (2H, m), 3.59(2H, t, J=6.6Hz), 3.87 (3H, s), 3.91 (3H, s).

IR (KBr) ν: 3525, 3400, 2925, 2850, 1480, 1460, 1430, 1370, 1190, 1120,1060, 940, 805, 520 cm⁻¹.

EXAMPLE A-151-O-[2,3-Dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl]-β-D-glucopyranoside

6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol(6.2 g) obtained in Example B-1 was dissolved in dichloromethane (40ml). O-(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl)trichloroacetimidate(R. R. Schmidt et al., Angew. Chem. Int. Ed. Engl., 19, 731 (1980)) (6g) was added, and the mixture was ice-cooled. Boron trifluoride diethylether (2 ml) was added with stirring, and the mixture was allowed toreact at the same temperature for 30 minutes. Then water (50 ml)containing sodium bicarbonate (2 g) was added. The organic layer wasseparated and concentrated under reduced pressure. The residue wasdissolved in tetrahydrofuran (50 ml), and tetrabutylammonium fluoridetrihydrate (2 g) was added. The mixture was stirred for 30 minutes.After concentration under reduced pressure, the residue was subjected tocolumn chromatography on silica gel and eluted with hexane/ethyl acetate(7:3). The eluate was concentrated under reduced pressure. The residuewas dissolved by adding methanol (30 ml) and tetrahydrofuran (15 ml)thereto. 1N Sodium hydroxide solution (40 ml) was added, and the mixturewas stirred at room temperature overnight. After concentrating thereaction mixture under reduced pressure, ethyl acetate (200 ml) wasadded and 1N hydrochloric acid solution (40 ml) was added underice-cooling. The ethyl acetate layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off. The crystals thus obtainedwere separated by filtration and recrystallized from methanol/ether toobtain the desired compound (1.2 g).

mp: 163°-165° C.

Elemental Analysis for C₂₅ H₄₂ O₁₀.0.2H₂ O Calcd.: C,59.32; H,8.44Found: C,59.34; H,8.63

NMR (DMSO-d₆) δ (ppm): 1.26 (16H, m), 2.03 (3H, s), 2.60 (2H, m), 3.72(3H, s), 3.77 (3H, s), 4.27 (2H, m), 4.71 (1H, d, J=7 . 4Hz ) , 4.91(1H, d, J=4.6Hz), 5.00 (1H, d, J=4.0Hz), 5.14 (1H, d, J=4.2Hz), 8.32(1H, s).

IR (KBr) ν: 2930, 2860, 1470, 1435, 1395, 1390, 1370, 1110, 1065, 1040,1020, 1000, 970, 925, 895, 650, 620 cm⁻¹.

[α]_(D) ²⁵ =-18.7° (c=1.215 MeOH)

EXAMPLE A-161-O-[2,3-Dimethoxy-1-hydroxy-6-(10-hydroxydecyl)-5-methylphenyl]-β-D-glucopyranoside

1-Acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-4-hydroxy-5-methylbenzene(2.1 g) obtained in Example A-5 was dissolved in dichloromethane (20ml). O-(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl)trichloroacetimidate(3 g) was added, and the mixture was ice-cooled. Boron trifluoridediethyl ether (1 ml) was added with stirring, and the mixture wasallowed to react at the same temperature for 30 minutes. Then water (20ml) containing sodium bicarbonate (0.5 g) was added. The organic layerwas concentrated under reduced pressure. The residue was dissolved inmethanol (10 ml), 1N sodium hydroxide solution (10 ml) was added, andthe mixture was stirred at room temperature overnight. Afterconcentration under reduced pressure, 1N hydrochloric acid solution (10ml) was added under ice-cooling, and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to obtain the desiredcompound as crystals (1.2 g).

mp: 130°-131° C.

Elemental Analysis for C₂₅ H₄₂ O₁₀ Calcd.: C,59.74; H,8.42 Found :C,59.42; H,8.53

NMR (CDCl₃ -DMSO-d₆) δ (ppm): 1.29 (16H, br.s), 2.23 (3H, s), 3.88 (3H,s), 3.90 (3H, s), 4.42 (2H, m), 4.61 (1H, d, J=7.0Hz), 6.58 (1H, s).

IR (KBr) ν: 2930, 2860, 1470, 1430, 1370, 1310, 1100, 1070, 1000 cm⁻¹.

[α]_(D) ²⁵ =-16.2° (c=0.993, MeOH)

EXAMPLE A-172,3-Dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methyl-1-(4-pyridylmethyloxy)benzenehydrochloride

A mixture of6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol(3.70 g) obtained in Example B-1, 4-chloromethylpyridine hydrochloride(1.96 g), potassium carbonate (5.00 g) and dimethylformamide (30 ml) wasstirred at room temperature for 16 hours. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was concentrated under reduced pressure, and the residuewas dissolved in tetrahydrofuran (30 ml). Tetrabutylammonium fluoridetrihydrate (1 g) was added, and the mixture was stirred at roomtemperature for 1 hour. The mixture was concentrated under reducedpressure. Methanol (50 ml) and 1N sodium hydroxide solution (10 ml) wereadded to the residue, and the mixture was stirred at room temperaturefor 16 hours. After concentration, the residue was subjected to columnchromatography on silica gel and eluted with ethyl acetate. The desiredfraction was concentrated. The residue was dissolved in ethanol (30 ml),and conc. hydrochloric acid (0.7 ml) was added. The crystals obtainedafter concentration under reduced pressure were separated by filtrationand washed with ether to obtain the desired compound (1.2 g).

mp: 145°-147° C.

Elemental Analysis for C₂₅ H₃₇ NO₅.HCl.0.1H₂ O Calcd.: C,63.91; H,8.20;N,2.98 Found: C,63.85; H,8.39; N,2.96

NMR (DMSO-d₆) δ (ppm): (16H, s), 2.06 (3H, s), 3.36 (2H, t, J=6.6Hz),3.73 (3H, s), 3.77 (3H, s), 5.19 (2H, s), 8.06 (2H, d, J=6.0Hz), 8.93(2H, d, J=6.0Hz).

IR (KBr) ν: 3325, 2925, 2850, 1640, 1600, 1510, 1470, 1430, 1380, 1360,1120, 1100, 1050, 970, 800 cm⁻¹.

EXAMPLE A-182,3-Dimethoxy-6-(10-hydroxydecyl)-4-(2-pyridylmethyloxy)-5-methylphenolhydrochloride

A mixture of1-acetoxy-6-(10-acetoxydecyl)-2,3-dimethoxy-4-hydroxy-5-methylbenzene(2.1 g) obtained in Example A-5, 2-chloromethylpyridine hydrochloride (2g), potassium carbonate (5 g) and dimethylformamide (15 ml) was stirredat room temperature for 16 hours. The reaction mixture was poured intowater, and the mixture was extracted with ethyl acetate. The organiclayer was concentrated under reduced pressure, and the residue wasdissolved in methanol (20 ml). Aqueous 1N sodium hydroxide solution (20ml) was added, and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure.The residue was subjected to column chromatography on silica gel andeluted with ethyl acetate, and the eluate was concentrated. The residuewas dissolved by adding ethanol (30 ml), and conc. hydrochloric acid(0.7 ml) was added. The crystals obtained after concentration underreduced pressure were separated by filtration using ether to obtain thedesired compound (1.7 g).

mp: 127°-130° C.

Elemental Analysis for C₂₅ H₃₇ NO₅.HCl.0.1H₂ O Calcd.: C,63.91; H,8.20;N,2.98 Found : C,63.84; H,8.27; N,2.96

NMR (DMSO-d₆) δ (ppm): 1.26 (16H, s), 2.08 (3H, s), 3.37 (2H, t,J=6.6Hz), 3.72 (3H, s), 3.76 (3H, s), 5.11 (2H, s), 7.70-8.80 (4H, m).

IR (KBr) ν: 2925, 2850, 1635, 1620, 1540, 1475, 1460, 1420, 1360, 1120,1100, 1060, 1005, 965, 770 cm⁻¹.

REFERENCE EXAMPLE 112,3-Dimethoxy-5-methyl-6-(10-trityloxydecyl)hydroquinone

2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methylbenzoquinone (33.8 g) wasdissolved in dichloromethane (250 ml). Trityl chloride (30 g) followedby triethylamine (10 g) was added, and the mixture was stirred at roomtemperature overnight. Then water (250 ml) containing sodiumhydrosulfite (40 g) was added, and the mixture was stirred at roomtemperature for 1 hour. The organic layer was separated, dried overanhydrous magnesium sulfate and concentrated under reduced pressure toobtain the desired compound (80.4 g).

NMR (CDCl₃) δ (ppm): 1.25 (16H, br.s), 2.15 (3H, s), 2.60 (2H, t,J=7.9Hz), 3.88 (6H, s), 5.25-5.32 (4H, m), 7.21-7.46 (15H, m).

EXAMPLE B-34-tert-Butyldiphenylsilyloxy-2,3-dimethoxy-5-methyl-6-(10-trityloxydecyl)phenol

2,3-Dimethoxy-5-methyl-6-(10-trityloxydecyl)hydroquinone (80.4 g) wasdissolved in dichloromethane (250 ml). tert-Butylchlorodiphenylsilane(26 ml) and imidazole (6.8 g) were added, and the mixture was stirred at40° C. for 21 hours. The reaction mixture was washed with water, driedover anhydrous magnesium sulfate and concentrated. The residue wassubjected to column chromatography on silica gel and eluted withhexane/ethyl acetate (9:1) to obtain the desired compound (40 g).

NMR (CDCl₃) δ (ppm): 1.26 (16H, br.s), 2.26 (3H, s), 2.59 (2H, t,J=7.9Hz), 2.90 (3H, s), 3.88 (3H, s), 3.04 (2H, t, J=6.6Hz), 5.29 (1H,s), 7.15-7.80 (15H, m).

IR (KBr) ν: 3500, 2925, 2850, 1740, 1590, 1460, 1425, 1380, 1265, 1190,1100, 1060, 970, 825, 745, 700 cm⁻¹.

EXAMPLE B-41-tert-Butoxycarbonyloxy-2,3-dimethoxy-4-hydroxy-5-methyl-6-(10-trityloxydecyl)benzene

A mixture of4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methyl-6-(10-trityloxydecyl)phenol(8 g), di-tert-butyl dicarbonate (3 g), triethylamine (1 g) anddichloromethane (20 ml) was stirred at 40° C. for 16 hours. Afterconcentration under reduced pressure, the residue was dissolved intetrahydrofuran (30 ml). Tetrabutylammonium fluoride trihydrate (2 g)was added, and the mixture was stirred at room temperature for 15minutes. The solvent was distilled off under reduced pressure, and theresidue was subjected to column chromatography on silica gel and elutedwith hexane/ethyl acetate (7:3) to obtain the desired compound (10 g).

NMR (CDCl₃) δ (ppm): 1.15-1.70 (16H, s), 1.55 (9H, s), 2.15 (3H, s),2.48 (2H, t, J=7.9Hz), 3.03 (2H, t, J=6.6Hz), 3.58 (3H, s), 3.90 (3H,s), 5.70 (1H, s), 7.15-7.75 (15H, m).

EXAMPLE A-192,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-4-nicotinoyloxyphenolhydrochloride

Nicotinoyl chloride hydrochloride (2 g) was added under ice-cooling to amixture of1-tert-butoxycarbonyloxy-2,3-dimethoxy-4-hydroxy-6-(10-trityloxydecyl)-5-methylbenzene(10 g), triethylamine (2 g) and dichloromethane (30 ml), and theresulting mixture was stirred at room temperature for 1 hour. Thereaction mixture was washed with water followed by an aqueous solutionof sodium bicarbonate, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was subjected to columnchromatography on silica gel and eluted with ethyl acetate/hexane (1:1)to obtain1-tert-butoxycarbonyloxy-2,3-dimethoxy-6-(10-trityloxydecyl)-5-methyl-4-nicotinoyloxybenzene(5.1 g). This compound was dissolved in methanol (35 ml). Concentratedhydrochloric acid (2 ml) was added, and the mixture was heated underreflux for 30 minutes. The mixture was concentrated under reducedpressure. Ether was added to the residue which was then separated byfiltration to obtain the desired compound (2.9 g).

mp: 135°-140° C. (HCl salt), mp: 84°-85° C. (free compound).

Elemental Analysis for C₂₅ H₃₅ NO₆.HCl Calcd.: C,62.30; H,7.53; N,2.91Found: C,62.08; H,7.54; N,2.90

NMR (DMSO-d₆) δ (ppm): 1.26 (16H, br.s), 2.01 (3H, s), 3.37 (2H, t,J=6.6Hz), 3.72 (3H, s), 3.74 (3H, s), 7.70-9.35 (4H, m).

IR (KBr) ν: 2925, 2860, 2400, 2120, 1980, 1760, 1615, 1470, 1430, 1380,1295, 1250, 1190, 1110, 1080, 1050, 1010, 740 cm⁻¹.

EXAMPLE A-202,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-4-(N-methyl-1,4-dihydropyridin-3-ylcarbonyloxy)phenol

2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methyl-4-nicotinoyloxyphenol (1.1 g)was dissolved in dimethylformamide (5 ml). Iodomethane (0.3 ml) wasadded, and the mixture was allowed to react at room temperature for 16hours. After concentration under reduced pressure, the residue wasdissolved in ethyl acetate (20 ml). Water (20 ml) containing sodiumhydrosulfite (1.74 g) and sodium bicarbonate (1.26 g) was added, and themixture was stirred at room temperature for 1 hour. The organic layerwas concentrated under reduced pressure, and the residue was subjectedto column chromatography on silica gel and eluted with ethyl acetate toobtain the desired compound (1.1 g) as an oil.

Elemental Analysis for C₂₆ H₃₉ NO₆.0.5H₂ O Calcd.: C,66.36; H,8.57;N,2.98 Found: C,66.40; H,8.87; N,3.04

NMR (CDCl₃) δ (ppm): 1.30-1.53 (16H, m), 2.03 (3H, s), 2.30 (3H, s),2.59 (2H, t, J=8.4Hz), 3.24 (2H, J=1.6Hz), 3.63 (2H, t, J=6.5Hz), 3.81(3H, s), 3.91 (3H, s), 4.85 (1H, m), 5.69 (1H, dd, J=l.6,SHz), 7.24 (1H,d, J=1.6Hz).

IR (KBr) ν: 2910, 2850, 1730, 1700, 1670, 1590, 1460, 1420, 1370, 1280,1250, 1170, 1095, 1030, 715 cm⁻¹.

EXAMPLE A-212,3-Dimethoxy-4-hydroxy-6-(10-hydroxydecyl)-5-methyl-1-(N-methyl-1,4-dihydropyridin-3-ylcarbonyloxy)benzene

A mixture of4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-6-(10-tirityloxydecyl)-5-methylphenol(4 g) obtained in Example B-3, nicotinoyl chloride hydrochloride (1 g),triethylamine (1.5 g) and dichloromethane (20 ml) was allowed to reactat room temperature for 16 hours. Then methanol (50 ml) and conc.hydrochloric acid (3 ml) were added to the reaction mixture, and themixture was heated under reflux for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved inethyl acetate and washed with an aqueous solution of sodium bicarbonate.The organic layer was concentrated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (30 ml). Tetrabutylammoniumfluoride trihydrate (1.2 g) was added, and the mixture was stirred atroom temperature for 1 hour. The solvent was distilled off under reducedpressure. The residue was dissolved in dimethylformamide (5 ml), andiodomethane (0.6 ml) was added followed by reaction at room temperaturefor 16 hours. After concentration under reduced pressure, the residuewas dissolved in ethyl acetate (30 ml). Water (30 ml) containing sodiumhydrosulfite (3.5 g) and sodium bicarbonate (2.5 g) was added, and themixture was stirred at room temperature for 1 hour. The organic layerwas concentrated under reduced pressure. The residue was subjected tocolumn chromatography on silica gel and eluted with ethyl acetate/hexane(1:1) to obtain the desired compound (1.0 g) as an oil.

Elemental Analysis for C₂₆ H₃₉ NO₆.0.5H₂ O Calcd.: C,66.36; H,8.57;N,2.98 Found: C,66.34; H,9.02; N,2.89

NMR (CDCl₃) δ (ppm): 1.26-1.55 (16H, m), 2.16 (3H, s), 2.43 (2H, m),2.99 (3H, s), 3.24 (2H, br.s), 3.64 (2H, t, J=6.5Hz), 3.81 (3H, s), 3.92(3H, s), 4.86 (1H, m), 5.65-5.80 (1H, m), 7.24 (1H, d, J=1.4Hz).

IR (KBr) ν: 3400, 2910, 2850, 1730, 1700, 1670, 1580, 1460, 1420, 1380,1315, 1260, 1160, 1100, 1040, 715 cm⁻¹.

EXAMPLE B-54-tert-Butyldiphenylsilyloxy-1-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene

6-(6-Carboxy-1-phenylhexyl)-2,3,5-trimethylbenzoquinone (29 g) wassuspended in ether (500 ml). Diazomethane/ether solution was added untilthe raw material was disappeared on thin-layer chromatography. Then theether layer was washed with water, dried over anhydrous sodium sulfateand concentrated. The concentrate was subjected to short columnchromatography using silica gel (500 ml) and eluted withhexane/dichloromethane (1:1) to obtain6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzoquinone (25.5 g)as an orange oil. This oil was dissolved in ether (200 ml) and stirredat room temperature for 1.5 hours with a solution containing sodiumhydrosulfite (52 g) in water (200 ml). The ether layer was separated andwashed with saturated brine, dried over anhydrous sodium sulfate andconcentrated to obtain6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylhydroquinone (25.5g). Then this compound was dissolved in dichloromethane (35 ml),imidazole (9.37 g, 2 eq.) was added, tert-butyldiphenylsilyl chloride(28.36 g, 1.5 eq.) was added dropwise with stirring at room temperatureand the mixture was allowed to react overnight. The deposited imidazolehydrochloride was filtered off, and the filtrate was concentrated. Theconcentrate was subjected to column chromatography on silica gel (800ml) and eluted with dichloromethane/hexane (2:1) to obtain the desiredcompound as a pale yellow viscous oil (46 g).

Elemental Analysis for C₃₉ H₄₈ O₄ Si Calcd.: C,76.93; H, 7.95 Found:C,76.97; H, 8.14

NMR (CDCl₃) δ (ppm): 1.04-2.29 (10H, m), 1.13 (9H, s), 1.96 (6H, s),2.03 (3H, s), 3.64 (3H, s), 4.21 (1H, t, J=7Hz), 7.14-7.74 (15H, m).

IR (film) ν: 3530, 1740 cm⁻¹.

EXAMPLE A-22 Monosodium6-(6-carboxy-1-phenylhexyl)-4-hydroxy-2,3,5-trimethylphenyl-1-sulfatemonotetra-n-butylammonium salt

4-tert-Butyldiphenylsilyloxy-1-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene(660 mg, 1.08 mM) was dissolved in dimethylformamide (5 ml). Sulfurtrioxide pyridine complex (650 mg, 4.08 mM) was added, and the mixturewas allowed to react at room temperature for 2 days. The reactionmixture was added to a mixture of methanol (20 ml) and 2N sodiumhydroxide solution (8 ml) under ice-cooling with stirring, and then themixture was allowed to react at room temperature for 2 hours. Themixture was stirred for 30 minutes while adding dry ice powder (20 g)little by little. The reaction mixture was concentrated to dryness, andtetrahydrofuran (30 ml), water (5 ml) and tetra-n-butylammonium fluoridetrihydrate (630 mg, 2.0 mM) were added to the residue. Then the mixturewas allowed to react at room temperature for 2 hours. The reactionmixture was concentrated to dryness. The residue was subjected to MCIgel (trade mark) CHP-20P column chromatography eluting with 70% methanoland then Sephadex (trade mark) LH-20 column chromatography eluting withwater and lyophilized to obtain the desired compound as colorless powder(59 mg).

mp: 130°-139° C.

Elemental Analysis for C₃₈ H₆₂ NO₇ SNa.4.1H₂ O Calcd.: C,58.98; H, 9.14;N,1.81 Found : C,58.80; H, 8.97; N,1.53

NMR (CD₃ OD) δ (ppm): 1.01 (9H, t, J=7Hz), 1.30-2.15 (22H, m), 1.69 (3H,s), 2.15 (3H, s), 2.35 (3H, s), 3.17-3.33 (6H, m), 5.16 (1H, t, J=SHz),7.00-7.34 (5H, m).

IR (KBr) ν: 3420, 1570, 1250 cm⁻¹.

EXAMPLE A-23 Monosodium6-(6-carboxy-1-phenylhexyl)-4-hydroxy-2,3,5-trimethylphenyl-1-sulfate

Monosodium6-(6-carboxy-1-phenylhexyl)-4-hydroxy-2,3,5-trimethylphenyl-1-sulfatemonotetra-n-butylammonium salt (30 mg, 0.0429 mM) was dissolved in water(15 ml). The solution was subjected to strong acid type ion exchangeresin (manufactured by Bio-Rad, AG50W-X8,100-200 mesh; Na type) column(φ3×7 cm) and eluted with water (200 ml). The desired fraction wasconcentrated. The residue was subjected to Sephadex (trade mark) LH-20column chromatography, eluted with water and lyophilized to obtain thedesired compound as colorless powder (16 mg).

mp: 195°-199° C.

Elemental Analysis for C₂₂ H₂₆ O₇ SNa.3.8H₂ O Calcd.: C,50.14; H, 6.62;S,6.08 Found: C,49.94; H, 6.50; S,6.08

NMR (CD₃ OD) δ (ppm): 1.10-2.29 (8H, m), 1.69 (3H, s), 2.15 (3H, s),2.34 (3H, s), 5.16 (1H, t, J=8Hz ) , 7.00-7.33 (5H, m).

IR (KBr) ν: 3440, 1615, 1560, 1240 cm⁻¹.

EXAMPLE A-24 Disodium6-(6-carboxy-1-phenylhexyl)-4-hydroxy-2,3,5-trimethylphenyl-1-O-β-D-glucopyranosiduronate

4-tert-Butyldiphenylsilyloxy-1-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene(881 mg, 1.447 mM) and methyl1-imino-2-trichloroethyl-O-α-D-2',3',4'-triacetylglucopyranosiduronate(1.01 g, 2.11 mM) were dissolved in dichloromethane (5 ml). Borontrifluoride ether complex (0.25 ml, 1.95 mM) was added with stirringunder ice-cooling, and the mixture was allowed to react at roomtemperature for 2 days. The reaction mixture was poured into ice-cooledwater (20 ml) and extracted with dichloromethane (10 ml) twice. Theextract was subjected to column chromatography on silica gel and elutedwith hexane/ethyl acetate (4:1) to obtain a pale yellow waxy material(636 mg). The material (610 mg) was dissolved in tetrahydrofuran (10ml), and a solution of tetra-n-butylammonium fluoride trihydrate (0.26g, 0.82 mM) in tetrahydrofuran (3 ml) was added. The mixture was allowedto react for 15 minutes. Methanol (15 ml) and 2N sodium hydroxidesolution (2.5 ml) were added, and the mixture was stirred for additional2 hours at room temperature. The reaction mixture was adjusted to pH 4.5with 6N hydrochloric acid followed by adjustment to pH 8.5 with sodiumbicarbonate, and the solvent was distilled off by concentration underreduced pressure. The concentrate was subjected to Sephadex (trade mark)LH-20 column chromatography and eluted with water. The desired fractionwas lyophilized to obtain the desired compound as white powder (75 mg).

mp: 204°-205° C. (dec.)

Elemental Analysis for C₂₈ H₃₄ O₁₀ Na₂.5H₂ O Calcd.: C,50.45; H, 6.65Found: C,50.70; H, 6.63

NMR (CD₃ OD) δ (ppm): 1.10-2.25 (10H, m), 1.70 and 1.78 (each 1.5H, s),2.12 and 2.15 (each 1.5H, s), 2.29 and 2.33 (each 1.5H, s), 3.01-3.61(4H, m), 4.45 and 4.67 (each 0.5H, d, J=8Hz), 5.08 (1H, t, J=8Hz),6.98-7.30 (5H, m).

IR (KBr) ν: 3400, 1610, 1560, 1410, 1060 cm⁻¹.

EXAMPLE A-251-Acetoxy-4-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene

4-tert-Butyldiphenylsilyloxy-1-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene(22.2 g, 36.46 mM) was dissolved in dichloromethane (200 ml) andtriethylamine (8.3 ml, 59.9 mM). Acetyl chloride (4.1 ml, 57.7 mM) wasadded under ice-cooling, and the mixture was stirred for 2 hours. Thereaction mixture was poured into ice-cooled water (100 ml) and stirredfor 20 minutes. Then the organic layer was washed with water, dried overanhydrous sodium sulfate and concentrated to obtain1-acetoxy-4-tert-butyldiphenylsilyloxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzeneas a pale yellow oil. This oil was dissolved in tetrahydrofuran (70 ml).1M tetra-n,butylammonium fluoride trihydrate/tetrahydrofuran solution(73 ml) was added, and the mixture was stirred at room temperature for 1hour. The reaction mixture was poured into ice-cooled water (150 ml) andextracted with ethyl acetate (150 ml). The organic layer was washed withwater followed by saturated brine and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was recrystallized from hexane to obtain the desired compound aspale yellow prisms (9.03 g).

mp: 146°-148° C.

Elemental Analysis for C₂₅ H₃₂ O₅ Calcd.: C,72.79; H, 7.82 Found:C,72.80; H, 7.52

NMR (CDCl₃) δ (ppm): 1.15-2.10 (8H, m), 1.94 (3H, s), 2.02 (3H, s), 2.17(3H, s), 2.25 (3H, s), 2.28 (2H, t, J=8Hz) , 3.66 (3H, s), 4.35 (1H,br.s), 4.62 (1H, br.s), 7.10-7.22 (5H, m).

IR (KBr) ν: 3480, 1750, 1740, 1210 cm⁻¹.

EXAMPLE A-26 Monosodium6-(6-carboxy-1-phenylhexyl)-1-hydroxy-2,3,5-trimethylphenyl-4-sulfate

1-Acetoxy-4-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene(308 mg, 0.747 mM) and sulfur trioxide triethylamine complex (700 mg,5.0 mM) were stirred in dimethylformamide (5 ml) at room temperature for15 hours and then at 43° C. for 5 hours. The reaction mixture was addedto a mixture of 2N aqueous sodium hydroxide solution (10 ml) andmethanol (20 ml) under ice-cooling, and the resulting mixture wasstirred at room temperature for 4 hours. The reaction mixture wasneutralized with 6N hydrochloric acid and concentrated to dryness. Theresidue was subjected to Sephadex (trade mark) LH-20 columnchromatography and eluted with water. The desired fraction wasconcentrated and lyophilized to obtain the desired compound as whitepowder (284 mg).

mp: 160°-164° C.

Elemental Analysis for C₂₂ H₂₇ O₇ SNa.3.3H₂ O Calcd.: C,51.02; H, 6.54Found: C,51.04; H, 6.28

NMR (CD₃ OD) δ (ppm): 1.15-2.30 (10H, m), 2.09 (3H, s), 2.28 (3H, s),2.59 (3H, s), 4.54 (1H, br.s), 7.02-7.29 (5H, m).

IR (KBr) ν: 3500, 1560, 1410, 1230 cm⁻¹.

EXAMPLE A-27 Disodium6-(6-carboxy-1-phenylhexyl)-1-hydroxy-2,3,5-trimethylphenyl-4-O-β-D-glucopyranosiduronate

1-Acetoxy-4-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene(300 mg, 0,727 mM) and methyl1-imino-2-trichloroethyl-O-α-D-2',3',4'-triacetylglucopyranosiduronate(600 mg, 1.25 mM) were dissolved in dichloromethane (5 ml). Borontrifluoride ether complex (0.12 ml, 0.96 mM) was added with stirringunder ice-cooling, and the mixture was allowed to react for 5 hours. Thereaction mixture was poured into ice-cooled water (30 ml) and extractedwith ethyl acetate (30 ml). The extract was concentrated and dissolvedin methanol (30 ml). 1N sodium hydroxide solution (7 ml) was added withstirring under ice-cooling, and the mixture was allowed to react at roomtemperature for 2 hours. The reaction mixture was adjusted to pH 6 with6N hydrochloric acid followed by adjustment to pH 7.9 with sodiumbicarbonate and concentrated. The concentrate was subjected to Sephadex(trade mark) LH-20 column chromatography eluting with water andlyophilized to obtain the desired compound as colorless powder (210 mg).

mp: 215°-220° C.

Elemental Analysis for C₂₈ H₃₄ O₁₀ Na₂.4H₂ O Calcd.: C,51.85; H, 6.53Found: C,52.03; H, 6.69

NMR (CD₃₀ D) δ (ppm); 1.20-2.30 (10H, m), 2.07 (3H, s), 2.26 (6H, s),3.38-3.61 (4H, m), 4.53 (1H, d, J=7Hz), 7.01-7.28 (5H, m).

IR (KBr) ν: 3430, 1610, 1560, 1410 cm⁻¹.

What is claimed is:
 1. A compound of the formula ##STR6## wherein R¹ andR² are the same or different and are methyl or methoxy, or R¹ and R² arejoined together to form the group of the formula: --CH═CH--CH═CH--;R³ ishydrogen or a protecting group selected from the group consisting ofacetyl, propionyl, butyryl, benzoyl, nicotinoyl, tetrahydropyranyl,methoxymethyl, ethoxyethyl, methoxyethoxymethyl, methylthiomethyl andtrityl; X is (1) hydrogen, (2) phenyl or naphthyl which areunsubstituted or are substituted by at least one substituent selectedfrom the group consisting of alkyl of 1-3 carbon atoms, alkoxy of 1-3carbon atoms and halogen, or (3) pyridyl which is unsubstituted or issubstituted by at least one substituent selected from the groupconsisting of alkyl of 1-3 carbon atoms, alkoxy of 1-3 carbon atoms andhalogen; R is a saturated or unsaturated bivalent straight-chainhydrocarbon group having up to 20 carbon atoms or a chemical bond; Y isa member selected from the group consisting of(1) hydrogen, (2)hydroxymethyl, (3) methoxymethyloxymethyl, (4) acetoxymethyl, (5)nitroxymethyl, (6) aminocarbonyloxymethyl, (7)methylaminocarbonyloxymethyl, (8) ethylaminocarbonyloxymethyl, (9)dimethylaminocarbonyloxymethyl, (10) phenylaminocarbonyloxymethyl, (11)morpholinocarbonyloxymethyl, (12) piperidinocarbonyloxymethyl, (13)carboxyl, (14) alkoxycarbonyl having 2 to 5 carbon atoms, (15)aryloxycarbonyl having 7 to 8 carbon atoms, and (16) aminocarbonyl whichis unsubstituted or is (15) aryloxycarbonyl having 7 to 8 carbon atoms,and (16) aminocarbonyl which unsubstituted or is substituted by(a)hydroxyl, (b) alkyl of 1 to 4 carbon atoms, (c) phenyl or naphthyl eachof which is unsubstituted or is substituted by hydroxyl, amino, nitro,halogen, methyl or methoxy, (d) morpholinocarbonyl, (e)thiomorpholinocarbonyl, or (f) piperidinocarbonyl; Ph is phenyl; andt-Bu is tert-butyl.
 2. A compound according to claim 1, wherein Y is(1)hydroxymethyl, (2) carboxyl, (3) alkoxycarbonyl having 2 to 5 carbonatoms, (4) aryloxycarbonyl having 7 to 8 carbon atoms, or (5)aminocarbonyl which is unsubstituted or is substituted by(a) hydroxyl,(b) alkyl having 1 to 4 carbon atoms, (c) phenyl or naphthyl each ofwhich is unsubstituted or is substituted by hydroxyl, amino, nitro,halogen, methyl or methoxy, (d) morpholinocarbonyl, (e)thiomorpholinocarbonyl, or (f) piperidinocarbonyl.
 3. A compoundaccording to claim 1, wherein both R¹ and R² are methyl, X is phenyl,and Y is (1) carboxyl, (2) alkoxycarbonyl having 2 to 5 carbon atoms,(3) aryloxycarbonyl having 7 to 8 carbon atoms or (4) aminocarbonylwhich is unsubstituted or is substituted by (a) hydroxyl, (b) alkylhaving 1 to 4 carbon atoms, (c) phenyl or naphthyl each of which isunsubstituted or is substituted by hydroxyl, amino, nitro, halogen,methyl or methoxy, (d) morpholinocarbonyl, (e) thiomorpholinocarbonyl or(f) piperidinocarbonyl.
 4. A compound according to claim 1 wherein R¹and R² are independently methyl or methoxy.
 5. A compound according toclaim 1, wherein X is hydrogen or phenyl which is unsubstituted orsubstituted by at least one substituent selected from the groupconsisting of alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbonatoms, and halogen.
 6. A compound according to claim 1 wherein R is asaturated or unsaturated bivalent straight-chain hydrocarbon group of 5to 8 carbon atoms.
 7. A compound according to claim 1, which is6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol.8. A compound according to claim 1, which is4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methyl-6-(10trityloxydecyl)phenol.9. A compound according to claim 1, which is4-tert-butyldiphenylsilyloxy-1-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene.